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FORMULATION AND EVALUATION OF
MONTELUKAST SODIUM CHEWABLETABLETS BY DIRECT COMPRESSION
METHOD
Dissertation submitted to
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY
Chennai - 32
In partial fulfillment for the award of the degree of
MASTER OF PHARMACY
IN
PHARMACEUTICS
Submitted by
Reg. No. 26113007
DEPARTMENT OF PHARMACEUTICS
J.K.K. NATTRAJA COLLEGE OF PHARMACY
KOMARAPALAYAM - 638183
TAMILNADU
APRIL-2013
Chapter I Introduction
Dept. of Pharmaceutics 1 J.K.K.Nattraja college of pharmacy
I. INTRODUCTION
FORMULATION AND EVALUATOIN OF MONTELUKAST SODIUM
CHEWABLE TABLETS BY DIRECT COMPRESSION METHOD
1. Introduction
A tablet is a compressed solid unit dosage form containing medicaments
with or without excipients. According to the Indian pharmacopoeia, pharmaceutical
tablets are solid flat or biconvex dishes prepared by compressing a drug or a mixture
of drugs, with or without excipients1,2
. They vary in shape and differ greatly in size,
shape and weight, depending on the amount of medicinal substances and the
intended mode of administration. It is most popular dosage form and 70% of the
total medicines are dispensed in the form of tablets. Tablets offer advantages over
both patient and manufacturers.
Tablets are most popular dosage form due to their simplicity and economy of
the manufacture, relative stability and convenience in packaging, shipping and
storage. For the patients, ease of manufacturing convenience in administration,
accurate dosing and stability compared to oral liquids, tamper proofness compared
to capsules, safe compared to parentral dosage forms make it a popular and versatile
dosage form3.
1.1 Properties of tablets4
Should be elegant product having its own identity while being free of defects
such as chips, cracks, discoloration and contamination.
Should have strength to withstand the rigors of shocks encountered in its
production, packing, shipping and dispensing.
Should have the physical stability to maintain its physical attributes over
time.
Must be able to release the medicament agent(s) in the body in a predictable
and reproducible manner.
Must have suitable chemical stability over time so as not to allow alteration
of medicinal agent(s).
Chapter I Introduction
Dept. of Pharmaceutics 2 J.K.K.Nattraja college of pharmacy
1.2 Tablet is one of the most popular oral dosage forms due to the following
potential advantages5,6,7
They are unit dosage form and they offer the greatest capabilities of all oral
dosage form for the greatest dose precision and the least content variability.
Cost is lowest of all oral dosage forms.
Lighter and most compact.
Easiest and cheapest to package and transport.
Product identification is easy and rapid requiring no additional steps when
employing an embossed and/or monogrammed punch face.
Easy to swallow with least tendency for hang-up.
Objectionable odor and bitter taste can be masked by coating techniques.
Suitable for large scale production.
Greatest chemical and microbial stability over all oral dosage form.
1.3 Disadvantages compared to other dosage forms8
Difficult to swallow in case of children and unconscious patients.
The tablets usually have insufficient mechanical strength. Hence, careful
handling is required.
The tablets may leave unpleasant taste and/or grittiness in mouth if not
formulated properly.
1.4 Pharmaceutical excipients used in tablets and capsules 9,10
The pharmaceutical industry is ever thirsty to satisfy patient’s therapeutical
needs and apart from active ingredients, excipients play a major role in formulation
development.
In addition to transporting the active drug to the site in the body where the
drug is intended to exert its action, excipients play an important part in the
manufacturing process. They may also be important for keeping the drug from being
released too early in the assimilation process in places where it could damage tender
tissue and create gastric irritation or stomach upset.
Disintegrant helps the drug to disintegrate into particles small enough to
reach the blood stream more quickly and few excipients protect the product's
stability so it will be at maximum effectiveness at time of use. In addition, some
excipients are used to aid the identification of a drug product.
Chapter I Introduction
Dept. of Pharmaceutics 3 J.K.K.Nattraja college of pharmacy
Some excipients are used simply to make the product taste and look better.
This improves patient compliance, especially in children. Although technically
"inactive" from a therapeutic sense, pharmaceutical excipients are critical and
essential components of a modern drug product. In many products, excipients make
up the bulk of the total dosage form. Apart from the drug’s active ingredient, other
essential components include diluents or fillers, binders, disintegrants, lubricants,
coloring agents and preservatives. Diluents or fillers are inert ingredients that can
significantly affect the chemical and physical properties of the final tablet thus
affecting the biopharmaceutical profile.
One classic example of this is calcium salts, which can be utilized as fillers,
which interfere with the absorption of tetracycline from the gastrointestinal tract.
This example emphasizes that excipients may not always be inert, as they may be
perceived. Usually tablets are designed so that the smallest tablet size which can be
conveniently compressed is formed. Thus, if the dose is small more diluents are
required and if the dose is high less diluents are required as not to increase the tablet
size, which might make it difficult to swallow.
Diluents selection should be made carefully as physical-chemical changes
might render the product unstable and might cause problems in manufacturing.
Binders are added to tablet formulations to add cohesiveness to powders thereby
providing the necessary bonding to form granules which under compaction form a
compact mass as tablet. In other words, binders are essential to achieve the
“hardness” of the tablet.
Binders are usually selected on basis of previous experience, particular
product needs, literature or vendor data or the preference of individual scientists or
manufacturing unit. The primary criterion when choosing a binder is its
compatibility with other tablet components. It must add sufficient cohesion to the
powders to allow for normal processing yet allow the tablet to disintegrate and the
drug to dissolve upon ingestion, releasing the active ingredients for absorption.
Disintegrant facilitate the breakup of a tablet after oral administration.
They can be added prior to granulation or during the lubrication step prior to
compression or at both processing steps. The effectiveness of many disintegrants is
affected by their position within the tablet. Since disintegration is the opposite
operation to granulation (agglomeration) and the subsequent formation of strong
Chapter I Introduction
Dept. of Pharmaceutics 4 J.K.K.Nattraja college of pharmacy
compacts, one must carefully weigh these two phenomena when designing a tablet.
Lubricants prevent sticking of the tablets to the tablet punches during the
compression phase of the tablet manufacturing process.
When lubricants are added to a powder mass, they form a coat around
individual particles which remains more or less intact during compression.
Lubricants are mostly hydrophobic. The presence of lubricant coating may cause an
increase in the disintegration time and a decrease in drug dissolution rate. The
choice of a lubricant may depend upon the type of tablet being manufactured,
dissolution, flow characteristics and requirements of the formulation in terms of
hardness, friability and compatibility.
Glidants are the materials that have good flow properties and poor
lubrication properties. Glidants improve the flow of powder into the tableting
machines for compaction. They act to minimize the tendency of a granulation to
separate or segregate due to excessive vibration. High speed tablet machine require
smooth even flow of material to die cavities (tablet mold). The uniformity of tablet
weights directly depends on how uniformly the die cavity is filled. In general many
materials commonly referred to as lubricants possess only a minimal lubricating
activity and are better glidants or anti-adherents.
Thus a blend of two or more materials may be necessary to obtain these
properties. Pharmacists should be familiar with the components of pharmaceuticals
products, beyond their active ingredients. In order to educate pharmacists on
excipients that are routinely used in the pharmaceutical industry, we decided to
examine the top 200 prescription, tablets and capsules products of 2003 and find out
how many or which excipients are used in each product.
The selection will cover both brand and generic drugs. Out of the 200
prescription drugs, the total numbers of inactive excipients used except for coating
and coloring agents were only 94. Although the list is composed on the top 200
drugs of 2003, very few blockbusters has been launched since then and still the
excipients in all remains the same.
Chapter I Introduction
Dept. of Pharmaceutics 5 J.K.K.Nattraja college of pharmacy
Table No: 1 Pharmaceutical excipients used in tablets and capsules
No Excipients No. of times used
out of 200
formulations
Use
1 Acacia 2
Emulsifying agent, stabilizing
agent, suspending agent, tablet
binder, viscosity-increasing agent
2 Alginate
1 Binder
3 Alginic Acid 1
Stabilizing agent, suspending
agent,tablet binder, Tablet
disintegrant,
Viscosity-increasing agent
4 Aluminum
Acetate 1 Antiseptic
5 Benzyl Alcohol 2 Antimicrobial preservative,
disinfectant,solvent
6 Butyl Paraben 1 Antimicrobial preservative
7
Butylated
Hydroxy
Toluene
1 Antioxidant
8 Citric acid 1 Disintegrant
9 Calcium
carbonate 1
Tablet and capsule diluents,
therapeutic agent
10 Candelilla wax 4 Binder
11 Croscarmellose
sodium 22 Tablet and capsule disintegrant
12 Confectioner
sugar 1
Sugar coating adjunct, sweetening
agent
13 Colloidal
silicone dioxide 22
Adsorbent,anticaking
agent,emulsionstabilizer,
glidant,suspending agent,tablet
disintegrant, thermal stabilizer,
viscosity-increasing agent
14 Cellulose 19
Adsorbent, suspending agent,
tablet and capsule diluents, tablet
disintegrant, Adsorbent, glidant,
suspending agent, tablet and
capsule diluents, tablet
disintegrant
15
Plain or
anhydrous
calcium
phosphate
3 Diluent
16 Carnuba wax 12 Binder
17 Corn starch 17 Binder
Chapter I Introduction
Dept. of Pharmaceutics 6 J.K.K.Nattraja college of pharmacy
No Excipients No. of times used
out of 200
formulations
Use
18
Carboxymethyl
cellulose
calcium
3
Stabilizing agent, suspending
agent, tablet and capsule
disintegrant, viscosity-increasing
agent, water-absorbing agent
19 Calcium
stearate 5 Tablet and capsule lubricant
20
Calcium
disodium
EDTA
1 Chelation
21 Copolyvidone 1 Film-former, granulating agent,
tablet binder
22 Castor oil
hydrogenated 4
Extended release agent, stiffening
agent,tablet and capsule lubricant
23
Calcium
hydrogen
phosphate
dihydrate
1 Diluent
24 Cetylpyridine
chloride 1
Antimicrobial preservative,
antiseptic, cationic surfactant,
disinfectant, solubilizing agent,
wetting agent
25 Cysteine HCL 1 Reducing Agent
26 Crosspovidone 20 Tablet disintegrant
27
calcium
phosphate di or
tri basic
7
Anticaking agent, buffer, nutrient,
dietary supplement, Glidant
28
Dibasic
Calcium
Phosphate
9 Diluent
29
Disodium
hydrogen
phosphate
1 Buffering agent
30 Dimethicone 1 Antifoaming agent, Emollient
31 Erythrosine
Sodium 2 Color
32 Ethyl Cellulose 3
Coating agent, flavoring fixative,
tablet binder, tablet filler,
viscosity-increasing agent
33 Gelatin 14
Coating agent, film-former,
gelling agent, suspending agent,
tabletbinder, viscosity-increasing
agent
Chapter I Introduction
Dept. of Pharmaceutics 7 J.K.K.Nattraja college of pharmacy
No Excipients No. of times used
out of 200
formulations
Use
34 Glyceryl
monooleate 2 Non-ionic surfactant
35 Glycerin
3
Antimicrobial preservative,
Emollient, humectants, plasticizer,
Solvent, sweetening agent, tonicity
Agent
36 Glycine 1 Tonicity agent
37 Glyceryl
monostearate 1
Emollient, emulsifying agent,
solubilizing agent, stabilizing
agent,sustained-release ingredient
38 Glyceryl
behenate 1
Coating agent, tablet binder,
lubricant
39
Hydroxy
propyl
cellulose
25
Coating agent, emulsifying agent,
suspending agent, thickening
agent,viscosity-increasing agent
40
Hydroxyl
propyl methyl
cellulose
45
Coating agent, film-former,
rate-controlling polymer for
sustained release, stabilizing
agent, suspending agent, viscosity-
increasing agent
41 Hypromellose 7
Coating agent, film-former,
rate-controlling polymer for
sustained release, stabilizing
agent, suspending
agent, tablet binder, viscosity-
increasing agent
42 HPMC Pthalate 1 Coating agent
43
Iron oxides or
ferric oxide 15 Color
44 Iron oxide
yellow 5
Color
45 Iron oxide red
or ferric oxide 6
Color
46
Lactose
hydrous or
anhydrous or
monohydrate or
spray dried
77
Binding agent, diluent for dry-
powder inhalers, lyophilization
aid, tablet binder, tablet and
capsule diluent.(lactose nhydrous)
Binding agent, diluent for dry-
powder inhalers,tablet binder,
tablet and capsule diluents(lactose
monhydrate), Binding agent,
diluent for dry-powder inhalations,
tablet and capsule diluents,
Chapter I Introduction
Dept. of Pharmaceutics 8 J.K.K.Nattraja college of pharmacy
No Excipients No. of times used
out of 200
formulations
Use
tablet and capsule filler(lactose
spray dried)
47 Magnesium
stearate 108 Tablet and capsule lubricant
48
Microcrystallin
e
cellulose
61 Adsorbent, suspending agent,
tablet diluents, tablet disintegrant
49 Mannitol 4
Sweetening agent, diluents,
tonicity agent, vehicle (bulking
agent) for lyophilized preparations
50 Methyl
cellulose 3
Coating agent, emulsifying agent,
suspending agent, tablet and
capsule
disintegrant, tablet binder,
viscosity-increasing agent
51 Magnesium
carbonate 2
Diluents
52 Mineral oil 3 Emollient, lubricant, oleaginous
vehicle, solvent
53 Methacrylic
acid copolymer 5 Coating
54 Magnesium
oxide 2 Diluents
55 Methyl paraben 5 Antimicrobial preservative
56 Povidone or
PVP 36
Disintegrant, dissolution aid,
suspending agent, tablet binder
57 PEG 40
Ointment base, plasticizer, solvent,
suppository base, tablet and
capsule lubricant
58 Polysorbate 80 19 Solubilizer
59 Propylene
glycol 10
Antimicrobial preservative,
disinfectant,humectants,
plasticizer,
Solvent, stabilizer for vitamins,
water-miscible cosolvent
60 Polyethylene
oxide 3
Mucoadhesive, tablet binder,
thickening agent
61 Propylene
paraben 4 Antimicrobial preservative
62 Polaxamer 407
or 188 or plain 3
Dispersing agent, emulsifying and
coemulsifying agent, solubilizing
agent, tablet lubricant, wetting
agent
Chapter I Introduction
Dept. of Pharmaceutics 9 J.K.K.Nattraja college of pharmacy
No Excipients No. of times used
out of 200
formulations
Use
63 Potassium
bicarbonate 1 Alkalizing agent, therapeutic agent
64 Potassium
sorbate 1 Antimicrobial preservative
65 Potato starch 1 Binder
66 Phosphoric
acid 1 Acidifying agent
67 Polyoxy140
stearate 1
Emulsifying agent, solubilizing
agent, wetting agent
68 Sodium starch
glycolate 20 Tablet and capsule disintegrant
69 Starch
pregelatinized 21
diluents, disintegrant,binder
(starch pregelatinized Glidant
( starch , potato, corn , wheat, rice)
70 Sodium
crossmellose 1 Disintegrant
71 Sodium lauryl
sulfate 13
Anionic surfactant, detergent,
emulsifying agent, skin penetrant,
lubricant, wetting agent
72 Starch 19
Glidant, diluents, disintegrant
binder.(starch , potato, corn ,
wheat, rice)
73 Silicon dioxide 14 Same as colloidal silicon dioxide
74 Sodium
benzoate 2
Antimicrobial preservative,
lubricant
75 Stearic acid 12 Emulsifying agent, solubilizing
agent, lubricant
76 Sucrose 9
Base for medicated confectionery,
granulating agent, sugar coating
adjunct, suspending agent,
diluents, sweetening agent,
viscosity-increasing agent
77 Sorbic acid 3 Antimicrobial preservative
78 Sodium
carbonate 1 Carbonating agent
79 Saccharin
sodium 1 Sweetening agent
80 Sodium
alginate 1
Stabilizing agent, suspending
agent, disintegrant, binder,
viscosity-increasing agent
81 Silica gel 1 Adsorbant
82 Sorbiton
monooleate 1
Solubilizer
Chapter I Introduction
Dept. of Pharmaceutics 10 J.K.K.Nattraja college of pharmacy
No Excipients No. of times used
out of 200
formulations
Use
83 Sodium stearyl
fumarate 4 Tablet and capsule lubricant
84 Sodium
chloride 3
Tablet and capsule diluents,
tonicity agent
85 Sodium
metabisulfite 1 Antioxidant
86 Sodium citrate
dihydrate 1
Alkalizing agent, buffering agent,
emulsifier, sequestering agent
87 Sodium starch 1 Binder
88
Sodium
carboxy methyl
cellulose
1
Disintegrant, binder, stabilizing
agent, suspending agent,
viscosity-increasing agent,
Water-absorbing agent.
89 Succinic acid 1 Acidity
90 Sodium
propionate 1 Antimicrobial preservative
91 Titanium
dioxide 49
Coating agent, opacifier, pigment
92 Talc 20 Anticaking agent, glidant,
diluents, lubricant
93 Triacetin 6 Humectant, plasticizer, solvent
94 Triethyl citrate 3 Plasticizer
In the tablet formulation, a range of excipients materials is normally required
along with the active ingredient in order to give the tablet the desired properties. For
example the reproducibility and dose homogeneity of the tablets are dependent on
the properties of the powder mass. The tablet should also be sufficient strong to
withstand handling, but should disintegrate after intake to facilitate drug release. The
choice of excipients will affects all these properties.
1.4.1 Filler
Fillers are used to make the tablets of sufficient for easy handling by the
patient and to facilitate production. Tablets containing a very potent active substance
would be very small without additional excipients. Good fillers will have good
compact ability and flow properties, acceptable taste will be non-hygroscopic and
good compact ability chemically inert. It may also be advantageous to have filler
that fragment easily, since this counteracts the negative effects of lubricant additions
to the formula.
Chapter I Introduction
Dept. of Pharmaceutics 11 J.K.K.Nattraja college of pharmacy
1.4.2 Binder
A material with a high bonding ability can be used as a binder to increase the
mechanical strength of the tablet. A binder is usually a ductile material prone to
undergo plastic deformation. Typically binder is polymeric material often with
disordered solid state structures. Of special importance is the deformability of the
peripheral parts of the binder particles. Thereby this group of materials has the
capacity of reducing interparticulate distance within the tablet, improving bond
formation. If the entire bulk of the binder particle undergoes extensive plastic
deformation during compression, the interparticulate voids will at least partly be
filled and the tablet porosity will decrease. This increase the contact area between
the particles which promote the creation of interparticulate bonds subsequently
increases the tablet strength. However, the effect of the binder depends on the both
its own properties and those of the other compounds within the tablet. A binder is
often added to the granulation liquid during wet granulation to improve the
cohesiveness and compactability of the powder particles, which assists formation of
granules. It is commonly accepted that binder added in dissolved form, during a
granulation process is more effectives than used in dry powder form during direct
compression.
1.4.3 Disintegrating agent
A disintegrants are normally added to facilitate the rupture of bonds and
subsequent disintegration of tablets. This increases the surface area of the drug
exposed to the gastrointestinal fluids incomplete disintegration can result in
incomplete absorption or a delay in the onset of action of the drug. There are several
types of disintegrations acting with different mechanisms
a) Promotion of the uptake of aqueous liquids by capillary forces.
b) Swelling in contact with water
c) Release if gases when in contact with water
d) Destruction of the binder by enzymatic action.
Starch is a traditional particles swells moderately in contact with water and
tablets disrupts so called superdisintegrants they are now commonly used since these
are primarily by extensive swelling they are effective in only small quantities. Cross
linked sodium carboxymethyl cellulose which is effective in concentrations of 2-4%.
Chapter I Introduction
Dept. of Pharmaceutics 12 J.K.K.Nattraja college of pharmacy
Larger particles of disintegrates have been found to swell to a greater extent and
with faster rate than finer particles resulting in more effectiveness disintegration.
1.4.3.1 Super Disintegrants11,12,13
Super disintegrants were increased demands for faster dissolution
requirements, there are now available. The major groups of compounds which are
used as superdisintegrants in many solid-dosage forms are as follows.
1.4.3.1.1Microcrystalline cellulose (Avicel)
Apart from its use in direct compression, microcrystalline cellulose is used as
a diluent in tablets prepared by wet granulation, as filler in capsules and for the
production of spheres. MCC tablets when exposed to increased humidity (75 %,one
week) resulted in a softening and swelling of plain microcrystalline cellulose tablets.
This change disappeared on removal of humid condition.
Table No: 2 Comparative properties of various grades of Avicel
AvicelGrade Features
pH-101 Most widely used for direct compression tabletting and wet
granulation
pH-102 Larger particle size, Compression properties similar to pH-101.
pH-103 Reduced moisture content and ideal for moisture-sensitive materials
pH-105
Finest particle size and may be used in direct compression of
coarser or granular or crystalline materials. It can be admixed with
pH-101 to achieve specific flow and /or compression properties
pH -200
Larger particle size which offers increased flowability within
minimum effect on compression characteristics. It can be used to
reduce tablet weight variation and to improve content uniformity.
Higher lubricant sensitivity and lower carrier capacity
pH-301 Higher density than its particle size equivalent, pH-01, providing
increased flowability, greater tablet weight uniformity
pH-302
Density characteristics similar to pH-102, pH-302. Offers increased
flowability, greater tablet weight uniformity and potential for
smaller tablets.
Chapter I Introduction
Dept. of Pharmaceutics 13 J.K.K.Nattraja college of pharmacy
1.4.4 Glidants, Anti-adherents and Lubricants
Glidants are added to increase the flow ability of the powder mass reduce
interparticular friction and improve flow in the hopper shoe and die of the tablet
machine. Anti-adherents can be added to decrease sticking of powder to the faces of
the punches and die walls during compaction and lubricants is added to decrease
friction between powder and die. Facilitating ejection of the tablet from the die
however addition of lubricants can have negative effect on tablet strength, since they
often reduces the creation of interparticular bond space. Further lubricants can also
slow the drug dissolution process by introducing hydrophobic films around drug and
excipients particles. These negative effects are especially pounced when long mixing
times are required. Therefore the amount of lubricants should be kept relatively low
and the mixing procedure kept short to avoid a homogenous distribution of lubricant
throughout the powder mass. An alternative approaches could then be to admix
granulated qualities of lubricant.
1.4.5 Flavor, sweetener and colorants
Flavor and sweeteners are primarily used to improve or mask the taste of the
drug with subsequent improvement in patient compliance. Coloring tablets has
aesthetic value that can improve tablet identification especially when patients are
taking number of different tablets at once.
1.5 Manufacturing
1.5.1 Tablet manufacturing methods14-24
Tablets are the unit solid dosage forms meant for oral use and are
manufactured by using tablet compression machines. The tabletting mixture that is
going to be compressed can be prepared by either of the three techniques- Wet
granulation, Dry granulation or direct compression. Each of the individual technique
mentioned above has their own advantages and disadvantages respectively.
(a.)Methods for tablet preparation
1. Granulation method.
a. Wet granulation.
b. Dry granulation.
2. Direct compression method.
Chapter I Introduction
Dept. of Pharmaceutics 14 J.K.K.Nattraja college of pharmacy
(b.) Steps involved in these methods
Wet granulation Dry granulation Direct compression
Blending Blending Blending
Wet massing and screening
Slugging/roller compaction
- Drying
- - Dry screening
Blending(with lubricant)
Blending
(with lubricant)
Blending
(with lubricant)
Compaction Compaction Compaction
1.5.1.1 Wet granulation
Wet granulation is the process in which a liquid binder is added to a powder
in a vessel equipped with any type of agitation that will produce agglomeration or
granules these granules after drying are compressed to tablet form.
1.5.1.2 Dry granulation
In this technique, there is no use of liquid. The process involves the
formation of flugs. Then these flugs are screened or milled to produce granules. The
granules formed are then compressed into tablet forms.
1.5.1.3 Direct compression
In general direct compression method involves the direct compaction of
tabletting mixture without the step of granulation, provided the tabletting mixture
should have enough flow properties and should form a robust tablet. For suppose, if
the tabletting mixture is not having good flow properties, we can either use direct
compression vehicles (DCV) for improving the flow and compatibility of tabletting
mixture or by subjecting the mixture for granulation process (wet or dry
granulation).
The invention of direct compression had increased the production of tablets
enormously all over the world due to its advantages over the other two techniques.
The main focus that must be kept in direct compression technique is about the use of
direct compression vehicle (DCV). Drugs must have good flow properties to be
suitable for direct compression along with good compaction properties. By using
DCVs, the flow properties of the drugs with poor flow can be improved and
Chapter I Introduction
Dept. of Pharmaceutics 15 J.K.K.Nattraja college of pharmacy
hence can be manufactured by direct compression technique. Drugs with minute
doses (potent drugs) as well as drugs with large doses are not suitable for direct
compression due to segregation problems and large tablet sizes respectively. Here
we mainly focused on the advantages and disadvantages of the direct compression
technique, essential properties of DCVs, some of the examples of DCVs and the
drugs that are suitable for direct compression technique.
Advantages of Direct compression
Cost Effectiveness: The prime advantage of direct compression over wet
granulation is economic since the direct compression requires fewer unit
operations. This means less equipment, lower power consumption, less
space, less time and less labor leading to reduced production cost of tablets.
Stability: Direct compression is more suitable for moisture and heat
sensitive APIs, since it eliminates wetting and drying steps and increases the
stability of active ingredients. Changes in Dissolution profiles are less likely
to occur in tablets made by direct compression on storage than in those made
from granulations.
Faster Dissolution: Disintegration or dissolution is the rate limiting step in
absorption in case of tablets with poorly soluble API prepared by wet
granulation. The tablets prepared by direct compression disintegrate into API
particles instead of granules that directly come into contact with dissolution
fluid and exhibits comparatively faster dissolution.
Less wear& tear of punches: The high compaction pressure involved in the
production of tablets by slugging or roller compaction can be avoided by
adopting direct compression. The chances of wear and tear of punches and
dies are less.
Other advantages: As ingredients are processed for a shorter period of time,
the chance for contamination is low. Due to fewer unit operations, the
validation and documentation requirements are reduced and will become
easier. Due to the absence of water in granulation, chance of microbial
growth is minimal in case of tablets prepared by direct compression.
Chapter I Introduction
Dept. of Pharmaceutics 16 J.K.K.Nattraja college of pharmacy
Limitations of Direct compression
Segregation: Direct compression is more prone to segregation due to the
difference in density of the API and excipients. The dry state of the materials
during mixing may induce static charges and lead to segregation. This may
lead to the problems like weight variation and content non-uniformity.
Cost: Directly compressible excipients are the speciality products produced
by spray drying, fluid bed drying, roller drying or co-crystallization. Hence,
the products are relatively costly than the respective raw materials.
Low dilution potential: Most of the directly compressible materials can
accommodate only 30-40 % of the poorly compressible active ingredients
like acetaminophen that means the weight of the final tablet to deliver the
500 mg of acetaminophen would be more than 1300 mg. The large tablets
may create difficulty in swallowing.
Lubricant sensitivity: Lubricants have more adverse effect on the filler,
which exhibit almost no fracture or shear on compression (e.g. starch 1500).
The softening effects as well as the hydrophobic effect of alkaline stearates
can be controlled by optimising the length of blending time to as little as 2-5
min.
Variation in functionality: There is a lack of awareness in some situations
that the excipients behave differently, depending upon the manufacturer so
much so that substitution from one source to that of another is not possible.
Hence, there is a need for greater quality control in purchasing of raw
materials to assure batch uniformity.
1.5.2 General formula for direct compression includes the following ingredients
1. Binder-Filler (DC-vehicles)
These DC vehicles (either binders or fillers) play an important role as that of
API in this method. In general, the terms binder and filler are always confusingly
used in direct compression. But, the major difference between these two is their
Dilution capacities. (Dilution capacity is the maximum proportion of the API that
can be compacted into an acceptable compact by the binder or filler.)Binders have
high dilution capacity as these are more compactible where fillers have less dilution
capacity due to their less compatibility nature. But, these values vary depending
upon the compacting ability of the API used. In general, dilution capacity values of
Chapter I Introduction
Dept. of Pharmaceutics 17 J.K.K.Nattraja college of pharmacy
binders and fillers are determined by using some reference materials which are
difficult to compact. Eg: ascorbic acid.
Based upon the solubility and disintegration properties of the Binders, these
can be classified as-
1. Binders
i. Soluble Binders: These are always non- disintegrating. Some of the examples are
Sugars, Ploy hydric alcohols etc.
ii. Insoluble Binders: These insoluble binders are again of two types-
a. Disintegrating (MCC, starch etc.)
b. Non-disintegrating (DCP)
When we use soluble filler, there will be rapid release of API from the tablet, but the
problem is that soluble erosion and release profile dominates the disintegration and
release profile. (We observed faster release patterns in case of MCC tablets
whencompared with similar formula where lactose is used instead of MCC).
Factors influencing the selection of optimum DC- vehicle
Properties of Powders. (particle size, shape, density, solubility)
Properties of compacts. (flow, compatibility)
Stability factors. (temperature and moisture effects)
Others. (cost, availability etc.)
2.Disintegrants
In general, we use less concentration of disintegrants in DC method when
compared with the wet granulation method which are nothing but super
disintegrants. This can be explained by following reasons-To minimize the softening
and flow properties of the tabletting mixture. The required uniform particle size of
API upon disintegration can be achieved only if the disintegrant used is uniformly
distributed in the tablet, which may be difficult when high loadings of API are used.
Also when we use soluble fillers, erosion followed by dissolution occurs instead of
disintegration, which can be avoided if we use more concentration of disintegrant or
super disintegrants. Some of the examples of super disintegrants are sodium starch
glycollate, crosspovidone, crosscarmellose etc. Though starch is not a super
disintegrant, we use it in DC because it can also be used as DC filler.
Chapter I Introduction
Dept. of Pharmaceutics 18 J.K.K.Nattraja college of pharmacy
3. Lubricants
We prefer hydrophilic lubricants over the hydrophobic ones in case of DC
method. This is because, hydrophobic ones (magnesium stearate) may form a film
around other ingredients used in the formula which may results in the decrease of
tablet hardness.
This problem can be overcome by following by –
Blending the tableting mixture (excluding lubricant) by high shear mixtures
and then adding the lubricant to this main blend with low shear mixing.
By carefully controlling the particle size and surface area of the lubricant
used.
Use of hydrophilic lubricants such as stearic acid, stearyl fumerate,
hydrogenated vegetable oils etc.
Some works showed that ejection force, hardness, disintegration and dissolution
times of MCC and lactose tablets were adversely effected depending upon the
lubricant mix time. Also the type of blender used effects the crushing strength of the
tablets. For example, crushing strength is much decreased for large industrial mixers
compared with small laboratory blenders when same concentration of lubricant is
used in both cases.
1.5.3 General requirements for Direct compression
Vehicles
In order to perform direct compression without any problems, we need to
consider certain parameters which are to be maintained in optimum range and are as
follows
Compactability
Flow properties
1. Compactability: In general, a good conventional tablet must have enough
hardness to withstand various stages of stress and must disintegrate and dissolve in
almost 60 minutes. So for the tablet to have enough hardness, it should have enough
compaction properties. If the API dose is low, then required compactability can be
achieved by using DC- filler.But if the API loadings are high with poor compaction
profile, then we must use a DC-binder to achieve a strong compact. (MCC is the best
DC- binder but can’t be used in case of low levels of insoluble API because the drug
may get encased in the MCC aggregates formed upon disintegration and the
Chapter I Introduction
Dept. of Pharmaceutics 19 J.K.K.Nattraja college of pharmacy
dissolution may become slower. In this case we can use soluble filler (Lactose) with
a superdisintegrant.) When we use more than one compactable agent (binders) then
we can expect both additive (MCC and lactose) and antagonistic effects.(cellulose or
starch with fast dissolving sugars like dextrose, sucrose and the result is poorer
compactability with long disintegration times). Also, as the crystal properties of
tabletting mixture increase, its compactability decreases. So, pure crystals are
generally inferior in terms of compactability. So, by increasing the amorphous
nature either by spray drying or co-crystallization we can improve the
compactability.
Eg: Spray drying of lactose results in small alpha monohydrate crystals that are held
together by amorphous glass. These agglomerates are superior to normal crystals in
terms of flow and compactability. Also, spray drying of acid hydrolyzate of
cellulose (MCC), agglomeration of starch and partially hydrolyzed starch, Co-
crystallization of sucrose with modifieddextrins.
2. Flow properties: “No flow, no tablets.” It is required in each and every step of
tablet preparation. Poor flow may result in difficulties for the compression mix to
flow from hopper to the die cavity which may cause weight variation problems.
Granulation step increases the flow in case of wet granulation method but in case of
DC we must use DC grade excipients for better flow. Proper flow can be attained by
using Glidiants at levels of 0.1-0.2%. Also if the flow exceeds the optimum range, it
may results in segregation of tablet ingredients, this will leads to content uniformity
problems.
Preparation of DC-vehicles
As we have already discussed that DC excipients are speciality products
prepared by modification of normal ingredients, these modification can be done in
two ways
Chemical modification
Ethyl cellulose, Methyl cellulose, HPMC, Na-CMC, Cyclodextrins etc.
Physical modification
Dextrates or compressible sugars, sorbitol, DCP etc.
Spray drying
MCC, Emdex, Spray dried Lactose etc.
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Dept. of Pharmaceutics 20 J.K.K.Nattraja college of pharmacy
Crystallization
Dipac etc.
Granulation
Tabletose (granulated lactose) etc.
Co-processing
Cellactose : MCC, Lactose
Ludipress : Lactose, PVP, Crosspovidone
Starlac : Lactose, Maize starch
Celocol : MCC, Calcium phosphate
1.6 Chewable Tablet 25-32
Tablet is most popular among all dosage forms existing today because
of convenience of self administration, compactness and easy manufacturing.25
Many patients express difficulty in swallowing tablets and hard gelatin
capsules, resulting in noncompliance and ineffective therapy.26
To overcome this weakness, scientists have developed innovative drug
delivery systems known as fast dissolving tablets.27
. United States Food and drug
administration (FDA) defined fast dissolving tablet (FDT) as “a solid dosage form
containing medicinal substance or active ingredient which disintegrate rapidly
usually within a matter of seconds when placed up on the tongue”.28
Their
characteristic advantages such as administration without water, patient compliance,
rapid onset of action, increased bioavailability and good stability make these
tablets popular as a dosage form of choice in the current market.29
Montelukast sodium is a leukotriene receptor antagonist (LTRA) used in
maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It
is usually administered orally. Montelukast sodium is freely soluble in ethanol,
methanol and water and practically insoluble in acetonitrile and its bioavailability
is 63%.30,31
In the present study an attempt had been made to prepare chewable tablets
of Montelukast sodium in the oral cavity with enhanced dissolution rate and hence
improved patient compliance. The basic approach used in the development of
Montelukast sodium chewable tablets by using co-processed super disintegrants
containing croscarmellose sodium was studied. The concept of formulating tablets
(FDT) of Montelukast sodium using co-processed superdisintegrants helps to
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Dept. of Pharmaceutics 21 J.K.K.Nattraja college of pharmacy
increase the water uptake with shortest wetting time and thereby decrease the
disintegration time of the tablets by simple and cost effective direct compression
technique. These systems may offer superior profile with potential mucosal
absorption, thus increase the drug bioavailability.
These systems are also called mouth dissolving tablets, melt-in-
mouth tablets, Reprimelts, porous tablets, Oro dispersible, quick dissolving or
rapidly disintegrating tablets. Montelukast (sodium salt) is potent, selective CysLT1
receptor anatagonist. It is indicated for the prophylaxis and chronic treatment of
asthma in adults and pediatric patients. The drug is commercially available in
various forms of once- daily oral dosage formulations including oral granules.
In addition to the therapeutic ingredients of pharmaceutical tablets
(commonly referred to as "actives"), materials inert and non-reactive with respect to
the actives (commonly referred to as "excipients") are added to the tablet
formulation to confer specific properties not related to the activity of the therapeutic
agents. Excipients such as diluents, binders, glidants, and lubricants are added as
processing aids to make the tableting operation more effective.
Other excipients such as microcrystalline cellulose are also added to improve the
compression of the tablets. Still other types of excipients added to pharmaceutical
tablets are those which enhance or retard the rate of disintegration of the tablet in
the patient, improve the taste of the tablet, (for example sweetening agents), or
impart a color to the tablets. In some instances such materials will provide more
than one of these benefits to the finished tablet. Although excipients are classified
as inert materials, they are only inert in the sense that they are not pharmaceutical
actives and do not provide a therapeutic effect in themselves, but they make
delivery of the therapeutic agent in the most effective manner possible.
Chewable tablets, regardless their geometry, represent a particular form of
oral dosage; they are intended to be chewed in the mouth by the patient and are not
intended to be swallowed intact. Many chewable formulations are intended to be
used to provide a known dosage of active to children or the people who either will
refuse to swallow an intact tablet or may have difficulty doing so. Such tablets are
often used to administer analgesics, antacids, antibiotics, anticonvulsants, vitamins,
and laxatives, for example. In addition to the foregoing, chewable tablets have
several advantages which make them the method of choice in delivering certain
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Dept. of Pharmaceutics 22 J.K.K.Nattraja college of pharmacy
types of therapeutic agents to an even greater population. One such advantage is that
certain types of tablets, because of the large size of the dosage, must be unusually
large and, therefore, difficult to swallow. In some cases the effectiveness of the
therapeutic agent is improved by the reduction in size that occurs during mastication
of the tablets before swallowing. Furthermore, patient compliance with the
prescribed therapy, such as antacid treatment, is enhanced by the use of smaller,
more convenient tablets which may be consumed when it is inconvenient to swallow
pills, for example, in the workplace. This is particularly true when the therapy would
otherwise involve a liquid suspension of the therapeutic agent which would be
inconvenient to transport, for example in chewable antacid tablets.
Excipients when added to chewable tablets must not only be inert in respect
of the active, preferably they provide pleasant mouthfeel and/or prevent tooth
packing, grittiness, and the like, without imparting any unpleasant characteristics to
the tablets as they are chewed. Microcrystalline cellulose in various forms.
Aggregates of coprocessed microcrystalline cellulose and guar, by which
these aggregates may be made and their physical and organoleptic properties. The
aggregates are disclosed as being useful as fat replacements in such food
applications as low-fat salad dressings and frozen dessert products. In this patent a
brief mention is made of several other possible uses for these materials including
controlled release agents, tableting excipients, flavor carriers, or bonding, bulking,
or encapsulating agents. Except for this mention, there is no enabling disclosure
directed toward their use as excipients nor suggestion that they possess unique
properties that might suit them for use in pharmaceutical tablets nor any indication
that they might provide extraordinary properties to a particular type of
pharmaceutical tablet, for example "chewable" tablets32
.
1.7 Asthma33-37
Asthma is a most common chronic inflammatory disease of the airways,
characterized by hyper responsiveness to a variety of stimuli. The role of circadian
rhythms in the pathogenesis and treatment of asthma indicates that airway resistance
increases progressively at night in asthmatic patients. Circadian changes are seen in
normal lung function, which reaches a low point in the early morning hours. The
worsening of asthma at night, commonly referred to as nocturnal asthma (NA). A
drug delivery system administered at bedtime. Asthma is chronic respiratory
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Dept. of Pharmaceutics 23 J.K.K.Nattraja college of pharmacy
disorder that causes difficulty in breathing when the airways become inflamed and
narrow. It is usually caused by allergies. The condition can be managed by
medication but sometimes, severe asthma attacks can be fatal.
Oral administration could be useful for the treatment of certain diseases, such as
asthma, gastric ulcer, hypertension, ischemic heart disease, arthritis, etc., which
exhibit circadian rhythms. Oral drug delivery is currently the gold standard in the
pharmaceutical industry where it is regarded as the safest, most convenient and an
economical method of drug delivery having the highest patient compliance.
1.7.1 Causes
In most cases of asthma in children, multiple triggers or precipitants exist,
and the patterns of reactivity may change with age. Treatment can also change
the pattern. Certain viral infections, such as respiratory syncytial virus
(RSV) bronchiolitis in infants, predispose the child to asthma.
Respiratory infections: Most commonly, these are viral infections. In some
patients, fungi (eg,allergic bronchopulmonary aspergillosis), bacteria
(eg, mycoplasmata, pertussis) or parasites may be responsible. Most infants
and young children who continue to have a persistent wheeze and asthma
have high immunoglobulin E(IgE) production and eosinophilic immune
responses (in the airways and in circulation) at the time of the first
viral (Upper Respiratory tract infection). They also have early IgE-mediated
responses to local aeroallergens.
Allergens: In patients with asthma, 2 types of bronchoconstrictor responses
to allergens exist.
Early asthmatic responses occur via IgE-induced mediator release from
mast cells within minutes of exposure and last for 20-30 minutes.
Late asthmatic responses occur 4-12 hours after antigen exposure and result
in more severe symptoms that can last for hours and contribute to the
duration and severity of the disease. Inflammatory cell infiltration and
inflammatory mediators play a role in the late asthmatic response. Allergens
can be foods, household inhalants (eg, animal allergens, molds, fungi,
cocroach allergens, dust mites), or seasonal outdoor allergens
(eg, mold spores, pollens, grass, trees).
Chapter I Introduction
Dept. of Pharmaceutics 24 J.K.K.Nattraja college of pharmacy
Irritants: Tobacco smoke, cold air, chemicals, perfumes, paint odors, hair
sprays, air pollutants, and ozone can initiate BHR by inducing inflammation.
Weather changes: Asthma attacks can be related to changes in atmospheric
temperature, barometric pressure, and the quality of air (eg:humidity,
allergen and irritant content).
Exercise: Exercise can trigger an early asthmatic response. Mechanisms
underlying exercise-induced asthmatic response remain somewhat uncertain.
Heat and water loss from the airways can increase the osmolarity of the fluid
lining the airways and result in mediator release. Cooling of the airways
results in congestion and dilatation of bronchial vessels. During
the rewarming phase after exercise, the changes are magnified because the
ambient air breathed during recovery is warm rather than cool.
Emotional factors: In some individuals, emotional upsets clearly aggravate
asthma.
Gastroesophageal reflux(GER):The presence of acid in
the distal esophagus, mediated via vagalor other neural reflexes,
can significantly increase airway resistance and airway reactivity.
Allergic rhinitis, sinusitis, and chronic URTI: Inflammatory conditions of
the upper airways (eg, allergic rhinitis, sinusitis, or chronic and persistent
infections) must be treated before asthmatic symptoms can be completely
controlled.
Nocturnal asthma: Multiple factors have been proposed to explain
nocturnal asthma. Circadian variation in lung function and inflammatory
mediator release in the circulation and airways (including parenchyma) have
been demonstrated. Other factors, such as allergen exposure and posture-
related irritation of airways (eg, GER, sinusitis) can also play a role. In some
patients, abnormalities in CNS control of the respiratory drive may
be present, particularly in patients with a defective hypoxic drive and
obstructive sleep apnea.
Chapter I Introduction
Dept. of Pharmaceutics 25 J.K.K.Nattraja college of pharmacy
1.7.2 Signs and Symptoms
Asthma is characterized by recurrent attacks of dyspnea, cough, and
expectoration of tenacious mucoid sputum, and usually wheezing. Symptoms may
be mild and may occur only in association with respiratory infection, or they may
occur in various degrees of severity to the point of being life-threatening.
Classic allergic (atopic) asthma usually begins in childhood and becomes
progressively more severe throughout life, although spontaneous remissions may
occur in adulthood. Hay fever often accompanies atopic asthma.
The acute attack is characterized by dyspnea usually associated with
expiratory wheezing that may be heard without a stethoscope. Cough may be present
but is usually not the predominant symptom. There is a small group of patients with
asthma in whom paroxysmal cough may be the predominant symptom. When
asthma becomes prolonged, with severe intractable wheezing, it is known as status
asthmaticus.
1.7.3 Essentials of Diagnosis
Recurrent acute attacks of dyspnea, cough, and mucoid sputum, usually
accompanied by wheezing.
Prolonged expiration with generalized wheezing and musical rales.
Bronchial obstruction reversible by drugs.
1.7.4 Laboratory Studies
The sputum is characteristically tenacious and mucoid, containing "plugs"
and "spirals." Eosinophils are seen microscopically. The differential blood count
may show eosinophilia. In severe, acute bronchospasm, arterial hypoxemia may be
present as a result of disturbed perfusion/ventilation relationships, alveolar
hypoventilation, or functional right-to-left shunts.
1.7.4.1 X-Ray Findings
Chest films usually show no abnormalities. Reversible hyper expansion may
occur in severe paroxysms, or hyper expansion may persist in long-standing cases.
Transient, migratory pulmonary infiltrations may be present. Severe attacks are
sometimes complicated by pneumothorax.
1.7.4.2 Differential Diagnosis
Distinguish wheezing from that due to other disorders such as bronchitis,
obstructive emphysema and congestive heart failure.
Chapter I Introduction
Dept. of Pharmaceutics 26 J.K.K.Nattraja college of pharmacy
Picture:1 Chronic Asthamatic Bronchiole.
1.7. 5 Treatment of the patients
Medications used to treat asthma are generally divided into 2 main
categories: relievers and controllers. Relievers are best represented by the inhaled
short-acting β2-agonists. These quick-acting bronchodilators are used to relieve
acute intercurrent asthma symptoms, only on demand and at the minimum required
dose and frequency.
Inhaled ipratropium bromide is less effective, but is occasionally used as a
reliever medication in patients intolerant of short-acting β2-agonists. Controllers (or
preventers) include anti-inflammatory medications, such as inhaled (and oral)
glucocorticosteroids, leukotriene-receptor antagonists, and anti-allergic or inhaled
nonsteroidal agents, such as cromoglycate and nedocromil. These agents
are generally taken regularly to control asthma and prevent exacerbations. Inhaled
glucocorticosteroids are the most effective agents in this category.
The controller group also includes some bronchodilators that are taken
regularly in addition to inhaled gluco-corticosteroids to help achieve and maintain
asthma control. These include the long-acting inhaled β2-agonists salmeterol and
formoterol, which are the first choice in this category, as well as theophylline and
ipratropium. The β2-agonists and ipratropium are considered of no significant
benefit in reducing airway inflammation.
Chapter I Introduction
Dept. of Pharmaceutics 27 J.K.K.Nattraja college of pharmacy
There is some evidence that theophylline may have immunomodulatory
effects, but the clinical significance of this remains to be demonstrated. Asthma
drugs are preferably inhaled, because this route minimizes systemic absorption and,
thus, improves the ratio of the therapeutic benefit to the potential side-effects. The
patient must have repeated instruction on how to use the inhaled medication. The
recently developed oral leukotriene-receptor antagonists have good safety and
tolerance profiles and are taken orally, which may help certain patients comply with
treatment.
Asthma medications should be used at the minimum dose and frequency
required to maintain acceptable asthma control; they should not be used as a
substitute for proper control of the environment. Asthma medications are considered
to be safe over many years when used appropriately. The participants in the asthma
consensus conference have reviewed the role of each category of medication. In the
following sections they describe briefly the mode of action, pharmacologic and
clinical profile, mode of administration and potential side-effects of these drugs.The
treatment may be divided into 2 phases: treatment of the acute attack and interim
therapy, which is aimed at preventing further attacks.
1.7.6 Asthma management
For all patients with asthma, monitoring should be performed on a continual
basis based on the following parameters, which helps in the overall
management of the disease.
Monitoring signs and symptoms of asthma: Patients should be taught to
recognize inadequate asthma control, and providers should assess control at
each visit.
Monitoring pulmonary function: Regularly perform spirometry and peak-
flow monitoring.
Monitoring quality of life and functional status: Inquire about missed work
or school days, reduction in activities, sleep disturbances, or change in
caregiver activities.
Monitoring history of asthma exacerbations: Determine if patients are
monitoring themselves to detect exacerbations and if these exacerbations are
self-treated or treated by health care providers.
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Dept. of Pharmaceutics 28 J.K.K.Nattraja college of pharmacy
Monitoring pharmacotherapy: Ensure compliance with medications and
usage of short-acting beta-agonists.
Monitoring patient-provider communication and patient satisfaction.
1.7.7 Drug Category
Bronchodilators
Albuterol, Levalbuterol, Salmeterol, Ipratropium And Theophylline
Leukotriene Receptor Antagonists
Montelukast (Singulair), Zafirlukast
Corticosteroids
Fluticasone, Triamcinolone, Beclomethasone ,Prednisone, Budesonide
Mast Cell Stabilizers
Cromolyn
Combination Beta-Agonist/Corticosteroid
Salmeterol/Fluticasone
5-Lipoxygenase Inhibitors
Zileuton
1.8 General guidelines for collection stability data38-40
In general case stability are defined in three types. The conditions are given
in the table that covered storage condition and time period of the study. Accelerated
study was done at 40oC+/- 2
oC/75% RH+/- 5%RH, to know the results of the study
in short duration of time. The results of accelerated stability were then extrapolated
to know the\e stability at ordinary conditions. Long term study in mainly done at
25oC +/- 2
oC/60
oC RH +/- 5% RH, and the results are collected after 12 months.
Sometimes intermediate stability studied at 30oC+/- 2
oC/60% RH+/- 5%RH, done
and data is collected after 6 months.
Chapter I Introduction
Dept. of Pharmaceutics 29 J.K.K.Nattraja college of pharmacy
Table No: 3 ICH Guidelines
Study Storage condition
Minimum time period
covered by data at
submission
Long term
25°C +/- 2°C/60
°C RH +/- 5% RH
or
30oC +/-2
oC/65
oC RH +/- 5% RH,
12 months
Intermediate 30oC +/- 2
oC/65
oC RH +/- 5% RH, 6 months
Accelerated 40oC +/- 2
oC/75
oC RH +/- 5% RH, 6 months
It is up to the applicant to decide whether long term 25oC +/- 2
oC/60
oC RH
+/- 5% RH or 30oC +/- 2
oC/65
oC RH +/- 5% RH is to be performed.
If 30oC +/- 2
oC/65
oC RH +/- 5% RH is long term there is no intermediate
condition.
1.8.1 Stability guidelines for different climatic zones
For convenience in planning and storage and for stability studies
international practice identifies four climatic zones, where are described in the
united states Europe and Japan are characterized by zones I and II. The values in are
based on observable temperature and relatively humidity’s both in and outside in the
rooms from which mean kinetic temperature and average humidity values are
calculated. Derived values are based on inspections of data of individual cities and
on allowances for a margin of safety in assignment of theses specified conditions.
Chapter – 2 Literature Review
Dept of Pharmaceutics 30 J.K.K.Nattraja college of pharmacy
2. LITERATURE REVIEW
Chewable tablet dosage forms continued to draw attention in the search for
improved patient compliance and decreased incidence of adverse drug reaction.
Many drugs exhibit bitter taste when orally administered and the bitter taste often
causes non-compliance of patients because of the discomfort. Therefore,
suppression of the bitter taste has been an important subject for chewable tablets
with simultaneous improvement in oral feeling.
Priyanka et al41
., has formulated and evaluated montelukast sodium chewable
tablets by wet granulation method using microcrystalline cellulose, croscarmellose
sodium, mannitol, magnesium stearate, hydroxypropyl cellulose, ferric oxide. The
compatability studies were carried out by mixing definite proportion of Montelukast
sodium and microcrystalline cellulose, croscarmellose sodium, mannitol,
magnesium stearate, hydroxypropyl cellulose, ferric oxide and cherry flavour,
1:1,1:2.5,1:3,1:5,1:10 and kept in glass vials which has stored at 50°C (three weeks).
Based on the optimization of parameters concluded that chewable tablet of
Montelukast sodium can be prepared by wet granulation method using
croscarmellose sodium as a superdisintegrants.
Kaur Harbir et al42
., has reported pharmaceutical tablets can produced three
methods viz. direct compression, dry granulation and wet granulation. Out of three
methods, direct compression is most convenient and cheaper method.
Swati J et al43
., designed and evaluated chewable tablet of levamisole (used in
treatment of worm infestations). As an anthelmintic, it probably works by targeting
the nematode nicotinergic acetylcholine receptor. In the market, levamisole tablets
are available in the form of tablets. The chewable tablets of levamisole were
prepared by using lactose or mannitol along with sodium starch glycolate in
concentration ratios especially for paediatric use. Sodium saccharin and vanilla were
used as sweetening agent and flavouring agent respectively. It was observed that the
formulation containing lactose shows less disintegration time than formulation
containing mannitol.
Kanaka et al44
., formulated and evaluated montelukast sodium chewable tablets
by different techniques. Montelukast sodium is used for prophylaxis and chronic
treatment of asthma. Montelukast sodium chewable tablets (5 mg) were prepared
Chapter – 2 Literature Review
Dept of Pharmaceutics 31 J.K.K.Nattraja college of pharmacy
and evaluated for the parameters such as average weight, hardness, tensile strength,
friability, in vitro dissolution, and assay. The study on the dissolution profile
revealed that product prepared from direct compression method had faster
dissolution rate while compared to remaining batches and marketed product. Assay
values were within the limits of 95 to 105%.
Kathiresan K et al45
., formulated and evaluated 5 batches of loratadine
chewable tablets. Loratadine, H1 receptor antagonist used in the treatment of allergic
rhinitis and urticaria. Results showed that thickness, weight variation, friability,
hardness, and content uniformity of all 5 formulations were within the acceptance
limits. But in the in-vitro dissolution study, formulations 1, 2, and 5 demonstrated
better cumulative drug release than formulations 3 and 4. However, cumulative drug
release of formulation 5 was comparable with innovator than formulations 1 and 2.
Hence the study concludes that loratadine chewable tablet formulated using avicel
CE 15 and starch paste showed better characteristics of chewable tablets.
Hiroyuki S et al46
., developed oral acetaminophen chewable tablets with
inhibited bitter taste. Various formulations with some matrix bases and coregents’
were examined for development of oral chewable tablets which suppressed the bitter
taste of acetaminophen, often used as an antipyretic for infants. Corn starch/lactose,
cacao butter and hard fat (Witepsol H-15) were used for matrix bases, and sucrose,
cocoa powder and commercial bitter-masking powder mixture made from lecithin
(Benecoat BMI-40) were used for corrigents against bitter taste. For the tablets made
of matrix base and drug, Witepsol H-15 best inhibited the bitter taste of the drug,
and the bitter strength tended to be suppressed with increase in the Witepsol H-15
amount. When the inhibitory effect on the bitter taste of acetaminophen solution was
compared among the corrigents, each tended to suppress the bitter taste; especially,
Benecoat BMI-40 exhibited a more inhibitory effect. Further, chewable tablets were
made of one matrix base and one corrigent, and of one matrix base and two kinds of
corrigents, their bitter taste intensities after chewing were compared. As a result, the
tablets made of Witepsol H-15/Benecoat BMI-40/sucrose, of Witepsol H-15/cocoa
powder/sucrose and of Witepsol H-15/sucrose best masked the bitter taste so that
they were tolerable enough to chew and swallow. The dosage forms best masking
bitter taste showed good release of the drug, indicating little change in
bioavailability by masking.
Chapter – 2 Literature Review
Dept of Pharmaceutics 32 J.K.K.Nattraja college of pharmacy
Maddi SS et al47
., designed sodium fluoride chewable tablets for dental caries.
Chewable tablets containing low dosage fluoride content were prepared using two
varities of celluloses and their in vitro parameters were evaluated. An eighteen
month clinical trial revealed that both these formulations were effective in
controlling the caries. However, ethyl cellulose is proved to be superior to
methylcellulose as a controlled release matrix material in controlling caries. Thus
this study recommends ethyl cellulose matrix tablets containing low fluoride content
is an efficacious and cost effective drug device in controlling dental caries.
Shajan et al48
., studied Montelukast sodium and Doxofylline bilayer tablet by
using disintegrant such as HPMC, Crosscarmellose sodium. The sustained release
layer of doxofylline HCl was developed by wet granulation technique using
polymers HPMC K100M and eudragit RL100 and the immediate release layer of
montelukast sodium by direct compression method using superdisintegrant
crosscarmellose sodium. The tablets were evaluated for their physical parameters.
All the values were found to be within acceptable limits. The in vitro release was
carried out using USP Type II apparatus. The optimized batch was subjected to
stability studies for 6 months at 40˚C ± 2 ˚C/ 75 % RH ± 5 % RH. The results
suggested that the developed bilayer tablets can be used as an alternative to the
conventional dosage form
Ganji Amarnath Reddy et al49
., studied oral fast disintegrating tablet of
Amlodipine Besylateusing different combination of superdisintegrants like
Croscarmellose sodium (Ac-Di-Sol), Sodium Starch Glycolate (Primogel), Cross
Povidone (Polyplasdone) and got better bioavailability within a short duration of
time with different formulations. For the masking of bitter taste we used
aspartame as sweetening agent. In this study instead of drug we prepared drug
solid dispersion so that drug’s solubility was enhanced.
Errolla Mahesh et al50
., has prepared and studied fast dissolving tablets of
Montelukast sodium by using novel co-processed superdisintegrants consisting of
crospovidone and sodium starch glycolate in the different ratios (1:1,1:2 & 1:3) in
vice versa. Montelukast sodium is a drug of choice in treatment of asthma and
allergic rhinitis. Drug compatibility with excipients was checked by FTIR studies.
After examining the flow properties of the powder blends the results were found to
be within prescribed limits and indicated good flowing property and it was subjected
Chapter – 2 Literature Review
Dept of Pharmaceutics 33 J.K.K.Nattraja college of pharmacy
to tablet compression. All the formulations were subjected to post compression
parameters like hardness and friability (≤1%), indicated that tablets had a good
mechanical strength and resistance. Drug content was found to be in the range of
93.51 to 98.79%. The wetting time is an important criteria for understanding the
capacity of disintegrants to swell in presence of little amount of water were found to
be in the range of 20 to 55 sec.
Mahalaxmi Rathnanand et al51
, has formulated and evaluated chewable Tablet
of Metformin HCl using Stevia by different techniques. The variation in the
dissolution rate of Metformin chewable tablets made by different techniques were in
the following order, direct compression non-aqueous granulation aqueous
granulation. Various evaluation parameters like thickness, hardness, friability,
weight variation and drug content of the formulations were found to be satisfactory.
Chewable immediate release metformin tablets DSC (Differential scanning
calorimetry) and IR (Infra-red) studies showed no interaction between drug and
excipients in optimized formulation. The optimized tablets found to be stable under
accelerated conditions for a period of one month.
M. Rajesh et al52
has formulated and characterized Albendazole chewable
tablets Albendazole (ABZ) is a benzimidazole derivative that has been widely used
in the treatment of worm infestations in both humans and animals. Albendazole
chewable tablets were prepared by wet granulation method using superdisintegrants
such as croscarmellose sodium and sodium starch glycolate. The formulations were
prepared and the granules were evaluated for pre-compression parameters such as
angle of repose, bulk density, tapped density, compressibility index and Hausner’s
ratio. The results showed that all the physical parameters were within the acceptable
limit. The stability study for the formulations showed no significance change in
disintegration time, drug content and percentage drug release after stored at
40°C±2°C/75%± 5% RH for the period of 30 days.
Mohd Abdul Hadi et al53
., has developed sustained release tablets of
Montelukast sodium by direct compression method using various polymers. The
drug excipient mixtures were subjected to pre-formulation studies. The tablets were
subjected to physicochemical studies, in- vitro drug release, kinetic studies and
stability studies. FTIR and DSC studies shown there was no interaction between
drug and polymers. The physicochemical properties of tablets were found within the
Chapter – 2 Literature Review
Dept of Pharmaceutics 34 J.K.K.Nattraja college of pharmacy
limits. Montelukast sodium is a leucotriene receptor antagonist used for the
maintenance treatment of asthma. The drug release from formulations was extended
for a period of 12 hrs. The kinetic treatment showed that the release of drug follows
first order models. The optimized formulations were subjected to stability studies
and shown there were no significant changes in drug content, physicochemical
parameters and release pattern. Results of the present study indicated the suitability
of the above mentioned polymers in the preparation of sustained release formulation
of Montelukast sodium.
Janugade et al54
., was prepared oral press-coated tablet by using direct
compression and wet granulation methods to achieve the predetermined lag time.
This press-coated tablet containing montelukast sodium in the inner core was
formulated with an outer barrier layer by different compositions of hydrophobic
polymer ethylcellulose and hydrophilic polymer low-substituted
hydroxypropylcellulose. The effect of formulation composition on the barrier
layer comprising both hydrophobic and hydrophilic excipients on the lag time of
drug release was investigated.
Halder A et al55
., has prepared Loperamide Hydrochloride chewable tablets by
wet granulation technique by using croscarmellose sodium, microcrystalling
cellulose, lactose monohydrate, magnesium stearate and SLS..etc. It has been found
that the prepared tablets showed good physical characteristics, drug content and
percentage of drug release.the present work aimed to prepare Loperamide
Hydrochloride chewable tablets in combined with simethicone and develop a new
sensitive and specific analytical procedure by HPLC suitable for application in a
drug quality control.the method of non-aqueous granulation and adsorption of
simethicone to dry powder blend improved hardness and provides good physical
appearance.
Chapter 3 Aim and Objective
Dept. of Pharmaceutics 35 J.K.K. Nattraja college of pharmacy
3. AIM AND OBJECTIVE
The goal of any drug delivery system is to provide a therapeutic amount of
drug to the proper site of the body, to achieve promptly and then maintain the
desired therapeutic drug concentration that elicits the desired pharmacological action
and to minimize the incidence and the severity of unwanted adverse effects.
For many decades, treatment of an acute disease or a chronic illness has been
mostly accomplished by delivering drugs using various pharmaceutical dosage
forms, including tablets, capsules, pills, suppositories, ointments, creams, liquids,
aerosols, and injectables as carriers. Amongst various routes of drug delivery, oral
route is perhaps the most preferred to the patients.
The oral route of drug
administration is the most important method of administering drugs for systemic
effects. Nevertheless, it is probable that at least 90% of all drugs used to produce
systemic effects are administered by oral route. It is very popular and successfully
used for delivery of drugs because of convenience and ease of administration,
greater flexibility in dosage form design, and ease of production and low cost of
such a system.
Chewable tablets are intend to be chewed in the mouth prior to swallowing
and are not intended to be swallowed intact. The purpose of chewable tablet is to
provide a unit dosage form of medication which can be easily administered to
children or to the elderly, who may have problem in swallowing a tablet intact. It is
also recommended to achieve rapid onset of action. Chewable tablets are preferred
for the drugs having high dose, the tablets of which cannot be swallowed.
Conversely, many patients are not able to tolerate the taste of many drugs
when formulated as liquid dosage forms, thus leading to poor patient compliance in
those cases. Lately recent developments in dosage form technology are
concentrating on presenting the patient with variable dosage alternatives which
provide good palatability and ease of administration at same time. This is especially
valid when the preparation is to be administered to an infant or to an elderly patient.
Hence it was decided to formulate Montelukast chewable tablets to improve
the compliance in children and elderly patients. Additionally, chewable tablet
facilitate more rapid release and hence more rapid absorption of active ingredients
and provide quick onset of action.
Chapter 3 Aim and Objective
Dept. of Pharmaceutics 36 J.K.K. Nattraja college of pharmacy
Montelukast sodium is a Leucotriene receptor antagonist used for the
treatment of asthma. Montelukast blocks the action of Leucotriene D4 on the
cysteinyl Leucotriene receptor in the lungs and bronchial tubes by binding to it. Its
biological half life 2.7 to 5.5 hrs.
The main objective of the present study was to formulate and evaluate
Montelukast chewable tablets dosage form at the dose of 5 mg and to study the
various formulation variables that affect the drug release by using the following
exicipients like Mannitol, Microcrystalline cellulose, Croscarmellose sodium,
Aspartame, Magnesium stearate, Cherry black, Euroxide and Red iron oxide .
Chapter – 4 Plan of work
Dept. of Pharmaceutics 37 J.K.K. Nattraja college of pharmacy
4. PLAN OF WORK
Preformulation studies
Design and development of chewable tablet by direct compression method
using superdsintigrants in different concentration. Prepared Chewable tablets of
Montelukast sodium will be subjected for the following evaluation parameters.
I. Pre-compression parameters
1. Angle of repose
2. Bulk density
3. Tapped density
4. Carr’s index
5. Hausner ratio
6. Compatibility study
II. Post-compression parameters
1. Appearence
2. Thickness
3. Hardness test
4. Friability test
5. Weight variation test
6. In-vitro dissolution studies
7. Stability studies
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 38 J.K.K. Nattraja college of pharmacy
5. DRUG AND EXCIPIENTS PROFILE
1. Montelukast sodium56-60
Montelukast is a Leucotriene Receptor Antagonist (LTRA) used for the
maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is
usually administered orally.
Montelukast blocks the action of leukotriene D4 on the cysteinyl leukotriene
receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the
bronchial constriction caused by the leucotriene and results in less inflammation.
Because of its method of operation, it is not useful for the treatment of acute asthma
attacks. Again because of its very specific locus of operation, it does not interact
with other allergy medications such as theophylline.
Structure
NCl
H
S
-NaOO
H
IUPAC Name: 2-[1-[[(1R)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-
[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropane]acetate.
Physical and chemical properties
Description : Hygroscopic, white to off-white powder
Empirical formula : C35H36ClNO3S
Molecular weight : 586.18324 g/mol (608.17 sodium salts)
Category : Antihistaminic
Chemical nature : Montulukast sodium is an sulfanylmethyl]
cyclopropyl]acetic acid
Solubility : Freely soluble in ethanol, methanol, water. Practically
insoluble in acetonitrile
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 39 J.K.K. Nattraja college of pharmacy
2. Microcrystalline Cellulose (Avicel)
Structural formula
Physical and chemical properties
Description : White, odourless, tasteless, crystalline powder
composed of porous particles.
Empirical formula : (C6H10O5)n, n=220
Molecular weight : 36,000(approx)
Functional Category: Tablet and capsule diluent, tablet disintegrant,
suspending and/or viscosity increasing agent.
Solubility : Insoluble in water, dilute acids and most organic
solvents, slightly soluble in 5% w/v NaOH solution.
Synonyms : Cellulose gel, Crystalline cellulose, Avicel PH101,
102, Density : Apparent density - 0.28g/cm3
Tap density - 0.43g/cm3
Applications:
Tablet binder/diluent (wet or dry granulation) : 5 to 20%
Tablet disintegrant : 5 to 15%
Tablet glidant : 5 to 15%
Antiadherent : 5 to 20%
O
O H
O C H 2 O H H
O H H
H O H
H
C H 2 O H
H
O
O H
H O H
H H
H
H H O
O H
H
O H
H C H
2 O H O
H O H
H C H 2 O H
H O
H O H
O H H
O H H
Microcrystalline Cellulose
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 40 J.K.K. Nattraja college of pharmacy
3. Magnesium Stearate
Structural Formula
Physical and chemical properties
Description : It is a fine, white, precipitated or milled, impalpable
powder of low bulk density, having a faint
characteristic odor and taste. The powder is greasy to
touch and readily adheres to the skin.
Empirical formula : C36H70MgO4
Molecular weight : 591.3
Functional category : Tablet and capsule lubricant.
Solubility : Practically insoluble in ethanol, ethanol (95%), ether
and water, slightly soluble in benzene and warm
ethanol (95%).
Synonyms : Metallic stearic; Magnesium salt.
Density : Bulk volume : 3.0-8.4 ml/g
Tapped volume : 2.5-6.2 ml/g
Applications : Tablet and capsule lubricant, glidant and antiadherent
in the concentration range of 0.25 to 5.0%.
4. Aspartame
Structural Formula
N-a-L-Aspartyl-L-phenyialanine 1-methyl ester
Physical and chemical properties
Description : Aspartame occurs as an off white, almost odorless
crystalline powder with an intensely sweet taste
Empirical Formula : C!4H18N2O5
Molecular Weight : 294.31
Functional Category : Sweetening agent.
Solubility : Soluble in water and organic solvents
Magnesium Stearate
CH3(CH
2)16
COO
CH3(CH
2)16
COO
Mg
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 41 J.K.K. Nattraja college of pharmacy
Synonyms : 3-Amino-N-(a-carboxyphenethyI)succin
amicacid IV-merhyl ester, 3-amino-N-(a-
methoxycarbonyl phenethyl) succinamic acid
Aspartyl phenylamine methyl ester methyl
N-a-L-aspartyl-l.-henylalaninate
Applications in Pharmaceutical Formulation or Technology
Aspartame is used as an intense sweetening agent in beverage products, food
products, and table-top sweeteners, and in pharmaceutical preparations including
tablets, powder mixes, and vitamin preparations, it enhances flavour systems and
can be used to mask some unpleasant taste.The approximate sweetening power is
180-200 times that of sucrose.Therapeutically, aspartame has also been used in the
treatment of sickle cell anemia.
Table No 4: Pharmacopeia Specifications.
Test PhEur2005 USPNF23
Characters + - Identification + +
Appearance of solution + -
Conductivity ≤ 30μS/cm -
Specific optical rotation +14.5-+16.5 +14.5-+16.5
Related substances + -
Heavy metals ≤ 10ppm ≤ 0.001%
Loss on drying ≤ 4.5% ≤ 4.5%
Sulfoted ash ≤ 0.2% ≤ 0.2%
Im purl lies + -
Transmittance - +
Limit of 5-benzyl-3,6-dioxo-
2-piperazineacetic acid
- ≤ 1.5%
Organic volatile impurities - +
Assay 98.0-102.0% 98.0-102.0%
+ indicates Presents, -- indicates Absent
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 42 J.K.K. Nattraja college of pharmacy
5. Mannitol
Structural Formula
D-Mannitol
Physical and chemical properties
Description
Mannitol is D-mannitol. It is a hexahydric alcohol related to mannose and
is isomeric with sorbitol. Mannitol occurs as a white, odorless, crystalline powder,
or free-flowing granules, it has a sweet taste, approximately as sweet as glucose
and half as sweet as sucrose, and imparts a cooling sensation in the mouth.
Microscopically, it appears as orthorhombic needles when crystallized from
alcohol. Mannitol shows polymorphism.
Empirical Formula : C6H14O6
Molecular Weight : 182.17
Functional Category : Diluent,diluent for lyphilizcd preparations,
Sweetening agent, tablet and capsule
diluents, tonicity agent.
Synonyms : Cordycepic acid,manna sugar, D-mannite,
mannite, Mannogem, Pearlitol
Applications in Pharmaceutical Formulation or Technology
Mannitol is widely used in pharmaceutical formulations and food products.
In pharmaceutical preparations it is primarily used as a diluent (10-90% w/w) in
tablet formulations, where it is of particular value since it is not hygroscopic and
may thus it is used with moisture-sensitive active ingredients.
Mannitol may be used in direct-compression tablet applications for which
the granular and spray-dried forms are available, or in wet granulations.
Granulations containing mannitol have the advantage of being dried easily.
Specific tablet applications include antacid preparations, glyceryl trinirrate
tablets, and vitamin preparations. Mannitol is commonly used as an excipient in
the manufacture of chewable tablet formulations because of its negative heat of
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 43 J.K.K. Nattraja college of pharmacy
solution, sweetness, and 'mouth feel’. In lyophilized preparations, mannitol (20-
90% w/w) has been included as a carrier to produce a stiff, homogeneous cake that
improves the appearance of the lyophilized plug in a vial. A pyrogen-free form is
available specifically for this use.
Mannitol has also been used to prevent thickening in aqueous antacid
suspensions of aluminum hydroxide (<7% w/v). It has been suggested as a
plasticizer in soft-gelatin capsules, as a component of sustained-release tablet
formulations, and as a carrier in dry powder inhalers. It is also used as a diluent
in rapidly dispersing oral dosage forms. It is used in food applications as a
bulking agent.
Therapeutically, mannitol administered parenterally is used as an osmotic
diuretic, as a diagnostic agent for kidney function, as an adjunct in the treatment
of acute renal failure, and as an agent to reduce intracranial pressure, treat cerebral
edema, and reduce intraocular pressure. Given orally, mannitol is not absorbed
significantly from the GI tract, but in large doses it can cause osmotic diarrhea.
Typical properties
Bulk Density : 0.430g/cm3
for powders
0.7g/cm3
for granules
Tapped density : 0.734g/cm3
for powders
0.8 g/cm3
for granules
Table No 5: Pharmacopeial specification for mannitol
Test JP 2001 Ph Eur2005 USP28
Characters - + +
Identification + + +
Appearance of solution + + -
Melting range 166-169 oC 165-170
oC 164-169
oC
Conductivity - ≤ 20μS/cm -
Specific optical rotation +137o - +145
o +23
o - +25
o +137
o - +145
o
Related substances - ≤ 0.1% -
Heavy metals ≤ 5ppm - -
Loss on drying ≤ 0.3 % ≤ 0.5 % ≤ 0.3 %
Acidity + - +
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 44 J.K.K. Nattraja college of pharmacy
Test JP 2001 Ph Eur2005 USP28
Assay ≥ 98.0 % 98.0-102.0% 96.0-101.5 %
Sulfate ≤ 0.01% - ≤ 0.01%
Arsenic ≤ 1.3 ppm - ≤ 1 ppm
Lead - ≤ 0.5 ppm -
Nickel + ≤ 1 ppm -
Chloride ≤ 0.007 % - ≤ 0.007 %
Reducing Sugars + ≤ 0.2% +
Residue on ignition ≤ 0.1% - -
Bacterial endo toxins - ≤ 4 IU/g(a)
-
Microbial contamination - ≤ 100/g -
6. Croscarmellose Sodium
Description
Croscarmellose sodium is a cross linked polymer of carboxymethyl
cellulose sodium. Cross linking makes it an insoluble, hydrophilic, highly absorbent
material, resulting in excellent swelling properties and its unique fibrous nature
gives it excellent water wicking capabilities. Croscarmellose sodium provides
superior drug dissolution and disintegration characteristics, thus improving
bioavailability of formulations.
Empirical Formula
Percentage of sodium chloride : 584.4VN/[(100–b)W]
Percentage of sodium glycolate :12.9w/[(100–b)W]
Degree of acid carboxymethyl substitution(A) : 1150M/(7102–412M–80C)
Degree of sodium carboxymethyl substitution(S) :(162+58A)C/(7102–80C).
Functional category : Disintegrant for Capsules, Tablets and Granules
Solubility : It is easily dispersed in water to form colloidal solutions.
Insoluble in alcohol, in ether, and in most other organic solvents.
NF category: Coating agent, suspending and/or viscosity-increasing agent,wet
binder, film-forming agent, release-modifying agent, disintegrant.
Synonyms :Croscarmellose sodium, modified,
croscarmellose natrium,
Cross-linked carboxymethylcellulose sodium
Chapter – 5 Drug and Excipient profile
Dept. of Pharmaceutics 45 J.K.K. Nattraja college of pharmacy
Applications
Croscarmellose sodium is used in oral pharmaceutical formulations as a
disintegrant for Capsules, Tablets and Granules. In tablet formulations,
Croscarmellose sodium may be used in both direct-compression and wet-granulation
processes. When used in wet granulations the Croscarmellose sodium is best added
in both the wet and dry stages of the process (intra- and extra granularly) so that the
wicking and swelling ability of the disintegrant is best utilized. Concentrations of up
to 5% w/w of Croscarmellose sodium may be used as a tablet disintegrant although
normally 2% w/w is used in tablets prepared by direct compression and 3% w/w in
tablets prepared by a wet-granulation process.
Table no:6 Croscarmellose sodium phycio-chemical properties
Croscarmellose Sodium
Identification
A Methylene blue - Blue fibrous mass
B 1-Nepthol - Red-purple colour at interface
C K-Antimonate-Sodium test positive
Ph 5.0 - 7.0
Loss on Drying, NMT % 10
Sodium Chloride and Sodium
Glycollate, sum NMT % 0.5
Heavy Metals, NMT % 0.001
Degree of Substitution 0.60 - 0.85
Content of Water Soluble
Material, % 1.0 - 10.0
Settling Volume, ml 10.0 - 30.0
Organic Volatile Impurities Meets the requirement
7. Euroxide Red Iron Oxide
Ferric oxide red is used in oral pharmaceutical formulations to impart a
distinctive appearance to the tablet of capsule. It is also useful in identification of
products with different strengths and aesthetic appearance etc.
8. Cherry Flavour
Cherry flavour functions as aflavour for improving the palatability of the
chewable tablet formulation. It also acts as a taste masking agent.
Chapter -6 Materials and Methods
Dept. of pharmaceutics 46 J.K.K. Nattaraja College of Pharmacy
6. MATERIALS AND METHODS
6.1 Source of data
The Physicochemical properties of drug will be collected from the national and
international journals, Internet facilities, Related articles, and Standard books from
library of the college.
6.2 Procurement of Drug and Excipients
The following materials and instruments used in the experiment are of laboratory grade.
Table No 7: Details of Materials used
Sl. No. Materials Grade Supplier
1. Montelukast sodium Pharma Shasun Drugs and Pharmaceuticals
limited
2. Mannitol Pharma Roquette Freres
3. Microcrystlline
cellulose Pharma FMC Biopolymer
4. Croscarmellose sodium Pharma FMC Biopolymer
5. Aspartame Pharma The Nutra Sweet Company
6. FLV ART Cherry
501027APO551 Pharma
The Sensient PharmaChem
Technology
7. Euroxide Red Iron
oxide (E7016) Pharma
The Sensient PharmaChem
Technology
8. Magnesium stearate Pharma Peter Greven Netherland
Chapter -6 Materials and Methods
Dept. of pharmaceutics 47 J.K.K. Nattaraja College of Pharmacy
6.3 Instruments and Equipments used
Table No 8: Details of equipments used
Sl. No. Instruments Manufacturer/ Suppliers
1. FTIR Spectrophotometer. Shimadzu 1800
2. Rotary Compression machine Clit Pilot press Chamnnda
3. Dissolution test Apparatus Electrolab, USP TDT 06P
4. Disintegration Tester Electro lab
5. Hot air Oven Lawrence & Mayo
6. Friability Tester Electro lab, USP EF 2
7. Hardness Tester Monsanto
8. Bulk density Apparatus (digital) KE India
9. Digital pH meter Hanna instrument
10. Vernier calliper Pico India Ltd
11. Digital Analytical balance Mettle Toledo
12. HPLC Shimadzu
Chapter 7 Experimental Work
Dept of Pharmaceutics 48 J.K.K. Nattraja college of pharmacy
7. EXPERIMENTAL WORK
7.1 Method of collection of data
To develop the formulation and estimation of Montelukast Sodium in
suitable pH solution.
Preformulation studies including solubility, compatibility with the
excipients.
To evaluate the physical properties of powder blend of tablet batches such as
angle of repose, bulk density, tapped density, compressibility index and
hausner’s ratio.
Evaluation of Montelukast Sodium chewable tablets for the parameters such
as description, hardness, friability, thickness, disintegration time, drug
content, drug release and uniformity of weight.
In vitro release characteristics of Montelukast Sodium from the chewable
tablets by dissolution test.
Short term stability studies of prepared formulations as per ICH guidelines.
Controlled room temperature: 25°C ± 2°C/60% RH ± 5% RH
Accelerated conditions: 40°C ± 2°C/75% RH ± 5% RH
Stress testing is conducted on a single batch of the tablets. The
study includes testing the effect of temperature at 50°C, 60°C, etc.
and humidity at 75% RH or greater as the drug is heat sensitive.
Packing system; The stability studies will be conducted on the
drug substance packaged in a container.
7.2 Physico-chemical properties of Montelukast Sodium
7.2.1 Appearance
The sample of Montelukast Sodium is white or almost white, odourless
crystalline powder.
7.2.2 Solubility
Montelukast sodium is freely soluble in water. The solubility in water is
8.553 mg/mL. The aqueous solubility as a function of pH at 37°C is studies at
various pH and the data presented in table.
Chapter 7 Experimental Work
Dept of Pharmaceutics 49 J.K.K. Nattraja college of pharmacy
Table No: 9 Solubility of Montelukast sodium in various media
Medium used pH of Media Solubility
(mg/mL)
Solubility (mg/250
mL)
Water 6.80 8.553 2138.25
0.5% SLS in water 6.00 15.114 3778.5
0.001N HCl 6.56 Insoluble Insoluble
0.01N HCl 2.95 Insoluble Insoluble
0.1N HCl 1.25 Insoluble Insoluble
pH 2.50 phosphate buffer 2.50 Insoluble Insoluble
pH 3.00 Phosphate buffer 3.00 Insoluble Insoluble
pH 3.50 Phosphate buffer 3.50 Insoluble Insoluble
pH 4.00 Phosphate buffer 4.00 Insoluble Insoluble
pH 4.50 Phosphate buffer 4.50 Insoluble Insoluble
pH 5.00 Phosphate buffer 5.00 Insoluble Insoluble
pH 5.50 Phosphate buffer 5.50 Insoluble Insoluble
pH 6.00 Phosphate buffer 6.00 Insoluble Insoluble
pH 6.50 Phosphate buffer 6.50 Insoluble Insoluble
pH 7.00 Phosphate buffer 7.00 Insoluble Insoluble
pH 7.50 Phosphate buffer 7.50 Insoluble Insoluble
pH 8.00 Phosphate buffer 8.00 0.001 0.001
SIF 6.80 Insoluble Insoluble
SGF 1.20 Insoluble Insoluble
pH 4.5 Acetate buffer 4.50 Insoluble Insoluble
7.2.3 Water content
Montelukast sodium drug substance was reported to be hygroscopic and the
water content was found to be 5.48%.
7.2.4 Hygroscopicity Study
1 gm of the drug was kept in pre-weighed petridish in duplicate and was
exposed to humidity condition of 40°C and 75% RH in order to assess the moisture
uptake tendency. The moisture gain was calculated from the weight gained by the
drug after periodic interval.Many compounds and salts are sensitive to the presence
Chapter 7 Experimental Work
Dept of Pharmaceutics 50 J.K.K. Nattraja college of pharmacy
of water vapour or moisture when compounds interact with moisture, they retain the
water by either bulk or surface adsorption, capillary condensation, chemical reaction
and, extreme cases a solution (deliquescence).
Moisture is also an important factor that can affect the stability of the drugs
and their formulations. Absorption of water molecules into a drug (or excipient) can
obtain includes hydrolysis.The influence that moisture has on stability depends on
how strongly it is bound, that is, it depends on whether the moisture is in a free or
bound state.
Table No:11 Hygroscopicity Classifications
S.No. Class Type Remarks
1 Class1 Non-hygroscopic Essentially no moisture increase
occur at RH below 90%
2 Class2 Slightly hygroscopic Essentially no moisture increase
occur at RH below 80%
3 Class3 Moderately hygroscopic Moisture content does not
increase more than 5% after
storage for one week at RH
below 60%
4 Class4 Hygroscopic Moisture content increase may
occur at RH as low 40 to 50%
If a compound is very hygroscopic, proper care should be taken to process it
in such a way to minimize the effect of moisture.
7.2.5 Identification of Montelukast sodium by IR
Chemical interactions between the drug and excipients may change the potency
and therapeutic efficacy of the drug. To investigate the possibilities of chemical
interaction between drug and excipients. FTIR spectra of pure drug and optimized
formulation were analyzed over the range 400-4000cm-1
.
Chapter 7 Experimental Work
Dept of Pharmaceutics 51 J.K.K. Nattraja college of pharmacy
Picture:2 IR spectrum of Montelukast sodium
7.3 Drug and Excipient Compatibility Studies 54,55
A drug excipient compatability study was performed to evaluate compatibility
of Montelukast sodium drug substance with different excipients. Excipients were
individually combined with the drug substance and exposed to solid-state stress
conditions (heat, light, heat/high humidity).
The compatibility of various drug substance / excipient combinations was
studied for all excipeints which were considered to find potential use in Montelukast
chewable tablet formulation. The table below summarizes the compatability study
results for the various excipients proposed to be employed in the formulation of
Montelukast chewable tablets.
Table No:10 Drug and Excipient Compatibility Studies
Sample Interval/ condition Assay (%) Water content (%)
Montelukast sodium
Appearance White powder
Initial 99.52 6.46
14 Days -40°C/75% RH 99.47 7.58
14 Days – 60°C 99.46 7.25
28 Days – 40°C/75% RH 99.38 8.22
28 Days – 60°C 99.28 7.00
Chapter 7 Experimental Work
Dept of Pharmaceutics 52 J.K.K. Nattraja college of pharmacy
Montelukast sodium
+ Microcrystalline
cellulose PH 102
Appearance White powder
Initial 99.59 6.18
14 Days – 40°C/75%RH 99.39 7.17
14 Days – 60°C 91.25 6.05
28 Days – 40°C/75% RH 99.12 6.91
28 Days – 60°C 87.10 6.32
Montelukast Sodium
+ Mannitol
Appearance White powder
Initial 98.42 0.85
14Days – 40°C/75%RH 99.36 1.11
14 Days – 60°C 99.00 0.74
28 Days – 40°C/75% RH 98.60 1.24
28 Days – 60°C 99.24 0.92
Montelukast Sodium
+Croscarmellose
sodium
Appearance White powder
Initial 99.58 1.97
14 Days – 40°C/75%RH 99.54 3.54
14 Days – 60°C 99.35 3.47
28 Days – 40°C/75% RH 99.49 4.64
28 Days – 60°C 99.07 4.75
Montelukast sodium
+ Aspartame
Appearance White powder
Initial 99.60 3.10
14 Days – 40°C/75%RH 99.35 4.79
14 Days – 60°C 97.98 3.69
28 Days – 40°C/75% RH 99.25 3.60
28 Days – 60°C 97.26 4.28
Montelukast sodium
+Red ferric oxide
Appearance Pink colored powder
Initial 99.59 6.17
14 Days – 40°C/75%RH 99.51 7.28
14 Days – 60°C 99.47 5.84
28 Days – 40°C/75% RH 99.41 7.47
28 Days – 60°C 99.29 5.69
Montelukast sodium
+Cherry Flavor
Appearance White powder
Initial 99.48 5.64
Chapter 7 Experimental Work
Dept of Pharmaceutics 53 J.K.K. Nattraja college of pharmacy
14 Days – 40°C/75%RH 99.38 7.58
14 Days – 60°C 98.50 6.32
28 Days – 40°C/75% RH 99.26 6.29
28 Days – 60°C 99.41 5.89
Montelukast sodium
+Magnesium stearate
Appearance White powder
Initial 99.41 6.40
14 Days – 40°C/75%RH 99.36 7.27
14 Days – 60°C 99.15 7.59
28 Days – 40°C/75% RH 99.24 7.74
28 Days – 60°C 99.01 7.80
All the powder characteristics were good and satisfied according to pharmacopeia.
A physical compatibility study was designed to determine the interaction of the
drug with various excipients. The samples that is drug alone and homogeneous
mixture of drug and each excipients were kept at accelerated conditions of 40oC in
sealed glass vials, and 40oC /75% RH in open and closed glass vials (punctured to
enable exposure to RH conditions for four weeks).These samples were then
periodically examined against a control sample kept at 4oC
25°C, 75% : Sealed vials
40°C, 75% RH (open) : Punched vials
40°C 75% RH (closed) : Sealed vials
60°C (close) : Sealed vials
The ratio for physical mixture of drug and the excipients was selected based
on the probable concentration of the excipients in stable formulation.
7.4 Pre-compression parameters for powder blend
7.4.1 Flow Properties
The flow properties of powder are critical for an efficient tabletting
operation. Interparticulate interactions that influence bulking properties of the
powder are also interaction that interferes with flow of powder. A comparison of
Chapter 7 Experimental Work
Dept of Pharmaceutics 54 J.K.K. Nattraja college of pharmacy
bulk density and tapped density gives a measure of relative importance of these
interactions in a given powder.
7.4.2 Bulk Density
Calculated amount of the model drug was introduced in a 100ml graduated
cylinder. Powder level was noted without compacting shows in table-19, Bulk
density was calculated using the following equation:
Bulk density = M/Vo
M =Mass of the test sample
Vo =Unsettled apparent volume
7.4.3 Tapped Density
Calculated amount of the model drug was introduced in a 100ml graduated
cylinder. Mechanically the cylinder was tapped using the tapped density apparatus
by raising the cylinder and allowing it to drop under its own weight that provides a
fixed drop of 14+_2 mm at a normal rate of 250 drops per minute. The cylinder was
tapped 1250 times initially and tapped volume measured. Tapped density was
calculated using the following equation:
Tapped Density = (M)/Vf
M= Mass of test sample
Vf = Final tapped volume
Since the interparticulate interaction that influence the bulking properties of
a powder causing interactions that interfere with powder flow, a comparison of the
bulk and tapped densities indicate a measure of the relative importance of these
interaction in a given powder. Such a comparison is often used as an index of ability
of the flow of property.
7.4.4 Compressibility Index (Carr’s index)
This parameter is the measure of propensity of powder to be compressed and
reflect the relative importance of interparticulate interaction shows in table-19.
100(TD – BD)
Carr’s Index = -----------------------
TD
Chapter 7 Experimental Work
Dept of Pharmaceutics 55 J.K.K. Nattraja college of pharmacy
7.4.5 Hausner Ratio
The Hausner ratio is a number that is used to correlate the flow ability of drug
substance.
Tapped density
Hausner ratio = --------------------------
Bulk density
Table No: 11 Flow ability of powder on the basis of Carr’s index and Hausner
Ratio
Carr’s Index Flow character Hausner ratio
<10 Excellent 1.00-1.11
11-15 Good 1.12-1.18
16-20 Fair 1.19-1.25
21-25 Passable 1.26-1.34
26-31 Poor 1.35-1.45
32-37 Very poor 1.46-1.59
>32 Very, very poor >1.60
The powder flow properties of API were studied to evaluate compressibility
of the drug since it is formulated as tablet. The result of various parameters of flow
properties of the API are shown in table.
7.4.6 Angle of Repose ()
Angle of repose is defined as the maximum angle possible between the
surface of a pile of the powder and horizontal plane. The frictional force in a loose
powder or granules can be measured by angle of repose.
tan = h / r, = tan-1
(h/r)
Where, is the angle of repose,
h is height of pile
r is radius of the base of pile
Different ranges of flow ability in terms of angle of repose are given in table no. 8.
Chapter 7 Experimental Work
Dept of Pharmaceutics 56 J.K.K. Nattraja college of pharmacy
Table No :12 Relationship between Angle of Repose () and flow properties.
Angle of Repose () (degrees) Flow
<25
25-30
30-40
>40
Excellent
Good
Passable
Very poor
Method
A funnel was filled to the brim and the test sample was allowed to flow
smoothly through the orifice under gravity. From the cone formed on a graph sheet
was taken to measure the area of pile, thereby evaluating the flowability of the
granules. Height of the pile was also measured.
7.5 Optimization of diluents, disintegrant and lubricant concentration:
Microcrystalline cellulose is a versatile ingredient playing multiple roles in
the formulations. Depending on the concentrations used, it can act as a diluent or
disintegrant. It aids in flow of the blend and is also an important ingredients in direct
compression techniques for tabletting. The optimization of microcrystalline cellulose
for Montelukast sodium chewable tablets 5 mg was done by varying the
concentrations of microcrystalline cellulose i.e 0 %, 5 %, 10 %,20 % and 27 %.
Croscarmellose sodium is used as a disintegrant in tablets and capsules
formulations. Three different trials were taken with various concentrations of
Croscarmellose sodium i.e. 0.5 %, 1% and 3 % in the formulation of Montelukast
sodium chewable tablets.
Magnesium stearate is used as a lubricant in tablets and capsules
formulations. Three different trials were taken with various concentrations of
magnesium stearate i.e. 1.25 %, 1.50 % and 1.75 % in the formulation of
Montelukast sodium chewable tablets.
Chapter 7 Experimental Work
Dept of Pharmaceutics 57 J.K.K. Nattraja college of pharmacy
Table No: 13 Percentage concentration of excipients used in the various formulations
Name of ingredients
%
F1
%
F2
%
F3
%
F4
%
F5
%
F6
%
F7
%
F8
%
F9
%
F10
Montelukast sodium 1.73 1.73 1.73 1.73 1.73 1.73 1.73 1.73 1.73 1.73
Mannitol 91.87 87.07 82.12 72.12 65.00 89.57 89.07 87.07 87.32 86.82
MCC(Diluent) 0.00 5.00 10.00 20.00 27.00 5.00 5.00 5.00 5.00 5.00
CCS (Disintegrant) 3.00 3.00 3.00 3.00 3.00 0.50 1.00 3.00 3.00 3.00
Aspartame 0.50 0.50 0.50 0.50 0.50 0.50 1.00 1.00 1.00 1.00
Cheery Black 1.00 1.00 1.00 1.00 1.00 1.00 0.50 0.50 0.50 0.50
Euroxide iron oxide 0.40 0.20 0.15 0.15 0.15 0.60 0.20 0.20 0.20 0.20
Magnesium stearate 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.25 1.75
Total tablet weight 100 100 100 100 100 100 100 100 100 100
Chapter 7 Experimental Work
Dept of Pharmaceutics 58 J.K.K. Nattraja college of pharmacy
7.6 Formulation design
The formula for preparation of Montelukast sodium chewable tablets by direct compression
Table No: 14 Qualitative and quantitative composition
Name of ingredients
Quantity in mg/ tablet and percentage
F 1 % F 2 % F 3 % F4 % F 5 %
Montelukast sodium 5.20 1.73 5.20 1.73 5.20 1.73 5.20 1.73 5.20 1.73
Mannitol 275.6 91.87 261.2 87.07 246.35 82.12 216.35 72.12 195.00 65.00
Microcrystalline cellulose 0.00 0.00 15.00 5.00 30.00 10.00 60.00 20.00 81.35 27.00
Croscarmellose sodium 9.00 3.00 9.00 3.00 9.00 3.00 9.00 3.00 9.00 3.00
Aspartame 1.50 0.50 1.50 0.50 1.50 0.50 1.50 0.50 1.50 0.50
Cheery Black 3.00 1.00 3.00 1.00 3.00 1.00 3.00 1.00 3.00 1.00
Euroxide iron oxide 1.20 0.40 0.60 0.20 0.45 0.15 0.45 0.15 0.45 0.15
Magnesium stearate 4.50 1.50 4.50 1.50 4.50 1.50 4.50 1.50 4.50 1.50
Total tablet weight 300 100 300 100 300 100 300 100 300 100
Continued…..
Chapter 7 Experimental Work
Dept of Pharmaceutics 59 J.K.K. Nattraja college of pharmacy
Name of ingredients
Quantity in mg/ tablet and percentage
F 6) % F 7 % F 8 % F 9 % F 10 %
Montelukast sodium 5.20 1.73 5.2 1.73 5.2 1.73 5.20 1.73 5.20 1.73
Mannitol 268.7 89.57 267.2 89.07 261.20 87.07 261.95 87.32 260.45 86.82
Microcrystalline cellulose 15.00 5.00 15.0 5.00 15.00 5.00 15.00 5.00 15.00 5.00
Croscarmellose sodium 1.50 0.50 3.00 1.00 9.00 3.00 9.00 3.00 9.00 3.00
Aspartame 1.50 0.50 3.00 1.00 3.00 1.00 3.00 1.00 3.00 1.00
CherryBlack 3.00 1.00 1.50 0.50 1.50 0.50 1.50 0.50 1.50 0.50
Euroxide red iron oxide 0.60 0.60 0.60 0.20 0.60 0.20 0.60 0.20 0.60 0.20
Magnesium stearate 4.50 1.50 4.50 1.50 4.50 1.50 3.75 1.25 5.25 1.75
Total tablet weight 300 100 300 100 300 100 300 100 300 100
Chapter 7 Experimental Work
Dept of Pharmaceutics 60 Nattraja college of pharmacy
7.7 Direction compression process 56
Tablets was decided to prepared by either Direct compression method.
Table No: 15 Composition of Core Tablet
Materials %w/w of the
total weight of
the Tablets
Mg/tablet Function
Montelukast Sodium 1.73 5.20 API
Mannitol 87.1 261.20 Diluent
Microcrystalline cellulose 5.0 15.00 Diluent
Croscarmellose sodium 3.0 9.00 Disintegrant
Aspartame 1.0 3.00 Sweetening Agent
Magnesium Stearate 1.5 4.5 Lubricant
Cherry Black 0.5 1.5 Flavouring agent
Euroxide Red Iron Oxide 0.2 0.6 Colorant
Total Tablet Weight 100 300 --
All ingredients should be taken within the limits
Chapter 7 Experimental Work
Dept of Pharmaceutics 61 J.K.K. Nattraja college of pharmacy
7.8 Manufacturing process of Montelukast chewable Tablets
Flow diagram of the manufacturing process
Process
Raw Materials
Dispensing
Deagglomeration sieve # 40ASTM
s
si
Pre-blending 10 minutes 10 RPM
s
si
Deagglomeration sieve # 40ASTM
s
si Blending 5 minutes at 10 RPM
Lubrication 5 minutes at 10 RPM
Compression
Lubricant
Chapter 7 Experimental Work
Dept of Pharmaceutics 62 J.K.K. Nattraja college of pharmacy
7.9 Evaluation of Tablets
7.9.1 Shape and colour58
Uncoated tablets were examined under a lens for the shape of the tablet and colour
was observed by keeping the tablets in light.
7.9.2 Thickness59
The crown thickness of individual tablet may be measured with a vernier caliper,
which permits accurate measurements and provides information on the variation between
tablets. Other technique employed in production control involves placing 5 or 10 tablets in
a holding tray, where their total crown thickness may be measured with a sliding caliper
scale. The tablet thickness was measured using vernier caliper.
7.9.3 Hardness test 60
Tablets require a certain amount of strength, or hardness and resistance to friability,
to withstand mechanical shocks of handling in manufacture, packaging and shipping. The
hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in
Kg/cm2. Three tablets were randomly picked from each formulation and the mean and
standard deviation values were calculated.
7.9.4 Friability test61
It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of
lamination or breakage when subjected to mechanical shock or attrition. The friability of
tablets was determined by using Roche Friabilator. It is expressed in percentage (%). Ten
tablets were initially weighed (Winitial) and transferred into friabilator. The friabilator was
operated at 25 rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed
again (Wfinal). The percentage friability was then calculated by,
W(initial)--w(final)
F = -------------------------×100
W(initial)
% Friability of tablets less than 1% is considered acceptable.
Chapter 7 Experimental Work
Dept of Pharmaceutics 63 J.K.K. Nattraja college of pharmacy
7.9.5 Weight variation test62
The tablets were selected randomly from each formulation and weighed individually
to check for weight variation. The U.S Pharmacopoeia allows a little variation in the
weight of a tablet. The percentage deviation in weight variation is shown in table no 10.
Table No :16 Percentage deviation in weight variation
Average weight of a tablet Percentage deviation
130 mg or less
More than 130 mg and less than 324 mg
324 mg or more
10
7.5
5
In all the formulations the tablet weight was more than130mg and less than 324
mg, hence 7.5% maximum difference allowed.
7.9.6 In-vitro disintegration time
The process of breakdown of a tablet into smaller particles is called as
disintegration. The in-vitro disintegration time of a tablet was determined using
disintegration apparatus as per I.P. specifications.
Method
For a drug to be absorbed from a solid dosage form after oral administration, it must
first be in solution, and the first important step toward this condition is usually the break-
up of the tablet, a process known as disintegration. The disintegration time of chewable
tablets was determined in accordance with the official “United status of pharmacopoeia
Chewable tablets” stating a maximum disintegration time of 5 minutes (USP 36).
One tablet in each of the 6 tubes of the basket is to be placed and the apparatus
subjected to run. The assembly should be raised and lowered between 50 cycles per
minute. The time in seconds taken for complete disintegration of the tablet with no
palpable mass remaining in the apparatus was measured and recorded.
Disintegration or more specifically dispersion times were measured in 900 ml purified
water according to the I.P. method without using disc at room temperature (25°C ± 2°C)
Chapter 7 Experimental Work
Dept of Pharmaceutics 64 J.K.K. Nattraja college of pharmacy
7.9.7 In-vitro dissolution studies63
In vitro release studies were carried out using tablet USP <711> dissolution test
apparatus. Two objectives in the development of in-vitro dissolution tests was to show
that,
i) Release of the drug from the tablet is as close as possible upto 100% and
ii) Rate of drug release is uniform from batch to batch and is the same as the release rate
from those proven to be bioavailable and clinically effective.
Summary of general in-vitro dissolution conditions employed throughout the study to
determine the in-vitro dissolution rate for all the formulation is given in table No 14.
Table No: 17 Summary of general dissolution conditions
Sl. No. Parameter Specifications
1. Dissolution medium 900 ml of 0.5%sodium
dodecyl sulphate
2. Temperature 37°C ± 5°C
3. Rotation speed 50 rpm
4. Volume withdrawn 10 ml sample at 5,10,15,20
and 30 minutes
5. Wavelength 220 nm
7.9.8 Dissolution by HPLC
Mobile phase
Solution A: Add 1.0 ml of ortho phosphoric acid (85% or 88%) in 1000 ml of water and
mix. Filter and degas.
Solution B: Acetonitrile
Mix the solution A & B in the ratio 40:60 and degas.
Dissolution medium preparation: 0.5 % sodium dodecyl sulphate
Chromatographic condition
Flow rate : 1.5 ml/minute
Injection volume: 50µl
Run time : 6 minutes
Wavelength : 220 nm
Chapter 7 Experimental Work
Dept of Pharmaceutics 65 J.K.K. Nattraja college of pharmacy
Standard and sample preparation
28.6 mg of Montelukast sodium which is equivalent to 27.5 mg of Montelukast,
transfer to 50 ml volumetric flask. Add 30 ml of methanol sonicate for 3 minutes to
dissolve. Dilute the volume with methanol and mix. Further dilute 5 ml to 50 ml with
dissolution medium and mix. Further dilute 5 ml to 50 ml with dissolution medium.
Calculation:
A Spl Std. wt Spl dilution % purity 100 585.18
% Dissolved = --------- x -------------- x ---------------- x --------------x -------- x ---------------
A Std Std. dilution Spl. weight 100 LC 608.18
7.9.9 Assay
Standard preparation
Weighed 52 mg of Montelukast sodium standard which is equivalent to 50 mg of
Montelukast and transfer into a 100ml volumetric flask. Add about 70 ml of mobile phase
and sonicate for 5 minutes to dissolve and make up with mobile phase. Dilute 10 ml of
stock solution to 50ml and mix.
Sample preparation
Weighed 10 tablets, transfer into 200 ml volumetric flask and add 150 ml
methanol, shake it for 2 mins and mechanically shake for about 20 minutes. Further
sonicate for 10 minutes with intermittent shaking and make up with mobile phase. Further
dilute 10 ml to 50 ml.
Calculation
A Spl Std. wt Spl dilution % purity 100 585.18
% Dissolved = --------- x -------------- x ---------------- x --------------x -------- x ---------------
A Std Std. dilution No. of tabs 100 LC 608.18
7.10 Stability Studies
Stability of a drug has been defined as the ability of a particular formulation, in a
specific container, to remain within its physical, chemical, therapeutic and toxicological
specifications.
The purpose of stability testing is to provide evidence on how the quality of a drug
substance or drug product varies with time under the influence of a variety of
Chapter 7 Experimental Work
Dept of Pharmaceutics 66 J.K.K. Nattraja college of pharmacy
environmental factors such as temperature, humidity and light and enables recommended
storage conditions, re-test periods and shelf lives to be established.
In the present study, the Montelukast Sodium Chewable Tablets are packed in
suitable packaging and stored under the following conditions for a period as prescribed by
ICH guidelines for accelerated studies.
(1) 25 ± 2°C/60±5%RH
(2) 40 ± 2°C/75±5%
The tablets were withdrawn after period of 1, 2 and 3Months and analyzed for physical
characterization (Appearance, hardness, friability, disintegration, dissolution etc) and drug
content.
Chapter 8 Result and Discussion
Dept of Pharmaceutics 67 J.K.K. Nattraja college of pharmacy
8. RESULT AND DISCUSSION
8.1 Solubility of Montelukast Sodium
Highest dose (5.2 mg of Montelukast sodium equivalent to 5 mg of
Montelukast) is insoluble over the entire pH range except in water and water
containing 0.5% SLS. The highest dose of 5.2 mg of Montelukast Sodium is soluble
in 5200 ml which is more than 250 ml. Montelukast sodium is considered as a low
soluble drug.
The solubility determination at various time intervals was not feasible as the
drug is insoluble in other pH except water and water containing 0.5 % SLS.
Table: 18 Solubility of Montelukast sodium in various media at different time
interval
Medium used pH of
Media
Solubility
(mg/ml)
(Initial)
Solubility
(mg/ml)
(12th
hour)
Solubility
(mg/ml)
(24th
hour)
Water 6.80 8.553 7.361 6.510
0.5% SLS in Water 6.00 15.114 15.083 15.000
8.2 Evaluation of Precompression Parameters
Table: 18 Powder characterization of formulations (F1- F10)
Formulation
code
Bulk density
(gm/ml)
(± SD)
Tapped
density
(gm/ml)
(± SD)
Carr’s index
(%)
(± SD)
Hausner’
s ratio
(± SD)
Angle of
repose
(± SD)
F1 0.526±0.094 0.666±0.120 21.02±0.03 1.26 29.56±0.04
F2 0.555±0.089 0.666±0.91 16.6±0.074 1.20 26.21±0.079
F3 0.588±0.074 0.714±0.069 17.64±0.065 1.21 27.89±0.051
F4 0.526±0.101 0.666±0.034 21.02±0.094 1.26 29.19±0.067
F5 0.476±0.093 0.588±0.113 19.04±0.093 1.23 27.97±0.084
F6 0.526±0.099 0.666±0.074 21.02±0.099 1.26 25.86±0.044
F7 0.50±0.107 0.558±0.07 14.9±0.107 1.17 25.52±0.021
F8 0.476±0.112 0.555±0.108 14.23±0.034 1.16 27.61±0.099
F9 0.50±0.094 0.625±0.043 20.0±0.0102 1.25 24.12±0.042
Chapter 8 Result and Discussion
Dept of Pharmaceutics 68 J.K.K. Nattraja college of pharmacy
Formulation
code
Bulk density
(gm/ml)
(± SD)
Tapped
density
(gm/ml)
(± SD)
Carr’s index
(%)
(± SD)
Hausner’
s ratio
(± SD)
Angle of
repose
(± SD)
F10 0.501±0.086 0.625±0.09 20.03±0.065 1.25 25.86±0.042
Mean±SD,(n=3)
For the all powder blend of the all formulated batches, the angle of repose
was found to be in the range of, thus indicating that the flow properties were fair.
Hausner’s ratio was less than1.26 for the all batches indicating good flow properties.
8.3 Evaluation of Tablets
Table: 19 Physical Evaluation of Montelukast Chewable Tablets
Parameter Weight
(mg)
Thickness
(mm)
Hardness
(kp)
Disintegration
time(mins’ and
sec’’)
Friability
(%)
F1 301-304 4.38-4.32 8-9 3’18’’-3’42’’ 0.18
F2 299-303 4.36-4.39 8-9 43’’-50’’ 0.18
F3 297-303 4.36-4.42 9-11 1’06’’-1’20’’ 0.08
F4 298-303 4.30-4.34 8-9 51’’-1’05’’ 0.01
F5 301-306 4.12-4.4 8-9 50’’-57’’ 0.14
F6 299-301 4.31-4.35 8-9 2’05’’-2’27’’ 0.25
F7 299-301 4.35-4.37 8-10 1’17’’-1’25’’ 0.18
F8 299-303 4.36-4.39 8-9 43’’-50’’ 0.18
F9 301-304 4.39-4.43 8-9 38’’-44’’ 0.13
F10 300-303 4.38-4.39 8-9 47’’-53’’ 0.25
Mean±SD,(n=3)
Chapter 8 Result and Discussion
Dept of Pharmaceutics 69 J.K.K. Nattraja college of pharmacy
8.4 Dissolution Profile of Marketed Tablets Vs Montelukast Chewable Tablets.
Table: 20 Dissolution Profile of Marketed Tablets Vs Montelukast Chewable
Tablets
Percentage of Drug Release at various time points
Time 5Minutes 10Minutes 15Minutes 20Minutes 30Minutes 45Minutes
Marketed
Drug 63.9 88.9 95.2 97.6 98.8 99.3
F1 62.2 93.8 95.2 95.2 95.3 95.3
F2 94.2 97.2 98.0 98.7 99.0 99.6
F3 94.0 94.6 95.2 95.2 95.3 95.0
F4 90.8 93.2 94.0 95.0 95.8 96.4
F5 90.7 93.7 94.5 94.8 95.2 95.0
F6 94.0 94.6 95.2 95.2 95.3 95.3
F7 98.8 99.7 99.9 99.9 100.3 100.2
F8 99.8 100.2 100.6 100.8 101.0 100.9
F9 94.9 97.3 97.9 97.8 97.6 98.3
F10 98.1 98.7 98.9 99.0 99.0 99.2
Chapter 8 Result and Discussion
Dept of Pharmaceutics 70 J.K.K. Nattraja college of pharmacy
Comparative dissolution profile of marketed tablets Vs Montelukast Chewable
Tablets 5 mg (F1 – F10)
Dissolution: HPLC Chromatogram
05
101520253035404550556065707580859095
100105110
0 5 10 15 20 25 30 35 40 45 50
% D
rug
Rel
ease
Time in Minutes
Comparative Dissolution profile of marketed sample with
Montelukast chewable tablets 5 mg
Marketed sample
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
Chapter 8 Result and Discussion
Dept of Pharmaceutics 71 J.K.K. Nattraja college of pharmacy
Stability studies
Table No: 21 Stability data of final formulation-F8 (Accelerated studies)
Storage Condition: Accelerated (40°±2°C/75±5%RH)
Parameters Limits 1 month 2 month 3 months
Appearance
Pink coloured,
round shaped
biconvex
tablets
Complies Complies Complies
Hardness 8-9 kp 8.5 8.4 8.5
Friability NMT 1% 0.18 0.19 0.18
Disintegration
time 5 minutes 48’’ 51’’ 49’’
Dissolution Q=80% at 20
min 99% 95% 98%
Assay 90% - 110% 103% 103.6% 102.8%
Table No: 22 Stability data of final formulation-F8 (Controlled Room
Temperature)
Storage Condition: Controlled Room Temperature (25°±2°C/60±5%RH)
Parameters Limits Initial 3 month
Appearance Pink coloured,
round shaped
biconvex tablets
Complies Complies
Hardness 8-9 kp 8.3 8.4
Friability NMT 1% 0.18 0.19
Disintegration time 5 minutes 50’’ 51’’
Dissolution Q=80% at 20 min 99% 98%
Assay 90% - 110% 102% 102.3%
Chapter 8 Result and Discussion
Dept of Pharmaceutics 72 J.K.K. Nattraja college of pharmacy
Discussion
The formulations were evaluated for pre-compression, post-compression
parameters and the values were found to be prescribed limits for all formulations.
The angle of repose indicates passable to good flow properties for all the
formulations. The results were presented in Table 18.
The compressed tablets were evaluated for various physical parameters such
as description, weight variation, thickness, hardness, friability, disintegration time
and in-vitro dissolution test. The results were presented in Table 19. Weight
variation was found in the range of 297 mg to 306 mg, Thickness was found in the
range of 4.12 mm to 4.42 mm, Hardness was found in the range of 8 to 11 kp for
the all the formulations indicating good mechanical strengths. The percentage
friability of all formulations were found in the range of 0.01% to 0.25%, and the
value the below 1% is an indication of tablet with good mechanical resistance. The
disintegration time of all formulations were found to be in the range of 38 seconds to
3 minutes 42 seconds. The drug content of the all tablets was found in the range of
95.2 % to 101 % of Montelukast sodium, which was with the acceptance criteria.The
results were presented in Table 20.
Montelukast sodium chewable tablets from all formulations and marketed
sample was subjected to in-vitro release studies. The formulation F1- F5 were
Prepared with MCC (0 %, 5%, 10%, 20% &27%), CCS (3%) and magnesium
stearate (1.5%). The release of the Montelukast sodium from formulations F1- F5
was 95.3%, 99.0%, 95.3%, 95.83% and 95.2 % respectively in 30 minutes.
The formulation F6- F8 was prepared with MCC (5%), CCS (0.5 %, 1 % and
3%) and magnesium stearate (1.5%). The release of the Montelukast sodium from
formulations F6- F8 was 95.3%, 100.3% and 101 % respectively in 30 minutes.
The formulation F9- F10 was prepared with MCC (5%), CCS (3%) and
magnesium stearate (1.25 % and 1.75 %). The release of the Montelukast sodium
from formulations F9- F10 was 97.6% and 99 % respectively in 30 minutes.
The drug release datas of the all formulations were compared with marketed
sample of Montelukast sodium. The release of the Montelukast sodium from the
Marketed sample was 98.8% at 30 minutes. From the above results of all
formulations were well within the limit (Q=80% at 30 minutes as per USP <711>,
2013).
Chapter 8 Result and Discussion
Dept of Pharmaceutics 73 J.K.K. Nattraja college of pharmacy
The formulation F8 was stored at 40°C±2°C/75 ± 5%RH, 25°C±2°C/60±
5%RH for 3 months and evaluated for any changes in the Physical appearance,
hardness, friability, disintegration time, in-vitro dissolution and Assay. The results
revealed that there was no significance change in the appearance, hardness,
friability, disintegration time, in-vitro dissolution and Assay after 3 months. The
stability study results were presented in Table 21 and 22.
Chapter 9 Summary and Conclusion
Dept. of Pharmaceutics 74 J.K.K. Nattraja college of pharmacy
9. SUMMARY AND CONCLUSION
From the above compiled data it was concluded that pharmaceutical tablets
Can be produced by three methods viz, direct compression, dry granulation and wet
granulation. Out of these three methods direct compression is the most convenient
and cheaper method.
Based on the optimization of the parameters concluded that chewable tablets
of Montelukast sodium can be prepared by direct compression method using
croscarmellose sodium as superdisintegrants. Chewable tablet of Montelukast
sodium with 3% of croscarmellose sodium and 5% of microcrystalline cellulose
shown better drug release of 101.0% at 30 minutes. The stability study of
Formulation F8 revealed that the drug was stable under accelerated and long term
stability conditions for 3 months. Hence the Formula F8 containing Montelukast
sodium 5 mg has been formulated as a chewable tablet by direct compression
method, which satisfied all the criteria for chewable tablets.
Chapter 10 Bibliography
Dept. of Pharmaceutics 75 J.K.K. Nattraja college of pharmacy
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